6,7-Dimethoxyquinazolines and therapeutic use thereof

ABSTRACT

Quinazoline compounds and methods for the treatment of cancer and for the treatment of allergic reactions.

FIELD OF THE INVENTION

[0001] This application relates to quinazoline compounds, compositionsand therapeutic methods for the treatment of cancers and treatment ofallergic disorders by administering quinazoline compounds.

BACKGROUND OF THE INVENTION

[0002] Quinazoline compounds have been suggested as useful compounds inthe treatment of cell growth and differentiation characterized byactivity of the human epidermal growth factor receptor type2 (HER2).See, for example, Myers et al., U.S. Pat. No. 5,721,237. Somequinazoline derivatives have been suggested as useful as anti canceragents for the treatment of specific receptor tyrosine kinase-expressingcancers, especially those expressing epithelial growth factor (EGF)receptor tyrosine kinase. See, for example, Barker et al., U.S. Pat. No.5,457,105. It is generally taught that quinazolines exert theiranti-tumor effects via tyrosine kinase inhibition. However, while somequinazoline compounds inhibit the growth of brain tumor cells, otherswith equally potent tyrosine kinase inhibitory activity fail to do so(Naria et.al., 1998, Clin Cancer Res. 4:1405-1414; Naria et al., 1998,Clin Cancer Res. 4:2463-2471).

[0003] Several tumors expressing EGF receptors are not killed byquinazoline compounds, whereas some tumors not expressing EGF recptorsare. Thus, the cytotoxic activity of quinazoline compounds cannot beattributed to the compound's tyrosine kinase inhibitory activity, andparticularly not to the compound's ability to inhibit EGF receptortyrosine kinase. A chemical structure-activity relationship determiningthe anti-cancer activity of quinazoline derivatives has not beenestablished.

[0004] Novel quinazoline compounds may provide potent new therapeuticmolecules for the treatment of disorders such as cancers. Methods ofusing both known and novel quinazoline compounds that employ anunderstanding of structure-function relationships are needed.

SUMMARY OF THE INVENTION

[0005] A series of quinazoline compounds were synthesized and analyzedfor therapeutic activities, including anti cancer activities,particularly against EGR receptor-negative leukemias. Specificquinazoline compounds of the invention were found to possess potent andspecific tyrosine kinase inhibitory activities affecting cellproliferation and survival. Quinazoline compounds of the invention aredemonstrated as useful for the treatment of specific tumors, includingbreast tumors, brain tumors, and leukemias, particularly EGFreceptor-negative leukemias, and to be particularly useful in thetreatment of multi rug resistant leukemias.

[0006] The invention provides novel quinazoline compounds of formula I,as disclosed below, as well as therapeutic methods utilizing thesecompounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIGS. 1A-1C are graphs showing cytotoxic activity offluoro-substituted dimethoxy quinazoline compounds (F-dmQ) againstleukemic NALM-6 cells.

[0008] FIGS. 2A-2C are graphs showing cytotoxic activity of F-dmQ onbreast cancer BT-20 cells.

[0009] FIGS. 3A-3F are photographs showing induction of apoptosis incancer cells by F-dmQ.

[0010]FIG. 4 is a bar graph showing adhesive properties of variouscancer cells to extracellular matrix proteins.

[0011] FIGS. 5A-5F are bar graphs showing the effect of F-dmQ on cancercell-adhesion to extracellular matrix (ECM) proteins.

[0012] FIGS. 6A-6E are photographs showing the effects of HI-P353 andHI-P364 on glioblastoma cell migration from spheroids.

[0013]FIGS. 7A and 7B are bar graphs showing the anti-invasive activityof fluoro-substituted quinazoline compounds (F-dmQ) against glioblastomaU373 and breast cancer MDA-MB-231 cells.

[0014] FIGS. 8A-8D are photographs showing depolymerizaton of actinstress fibers and microtubules by HI-P353.

[0015] FIGS. 9A-9I are photographs showing inhibition of actin stressfiber formation in glioblastoma cells by HI-P154.

[0016] FIGS. 10A-10C are graphs showing the inhibition of cancer cellgrowth in vivo by the quinazolines of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Definitions:

[0018] The terms “quinazoline”, “quinazoline compound”, and “quinazolinederivative” are used interchangeably in this application to meancompounds of formula I. All scientific and technical terms used in thisapplication have meanings commonly used in the art unless otherwisespecified. As used in this application, the following words or phraseshave the meanings specified.

[0019] Halo is fluoro, chloro, bromo, or iodo. Alkyl, alkanoyl, etc.,denote both straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto. (C₁-C₄)alkyl includes methyl, ethyl, propyl, isopropyl, butyl,iso-butyl, and sec-butyl; (C₁-C₄)alkoxy includes methoxy, ethoxy,propoxy, isopropoxy, butoxy, iso-butoxy, and sec-butoxy; and(C₁-C₄)alkanoyl includes acetyl, propanoyl and butanoyl.

[0020] As used herein, “pharmaceutically acceptable carrier” means anymaterial which, when combined with the compound of the invention, allowsthe compound to retain biological activity, such as the ability topotentiate antibacterial activity of mast cells and macrophages.Examples include, but are not limited to, any of the standardpharmaceutical carriers such as a phosphate buffered saline solution,water, emulsions such as oil/water emulsions, and various types ofwetting agents. Compositions comprising such carriers are formulated bywell known conventional methods (see, for example, Remington'sPharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Co.,Easton, Pa.).

[0021] The term “conjugate” means a compound formed as a compositebetween two or more molecules. More specifically, in the presentinvention, the quinazoline derivative is bonded, for example, covalentlybonded, to cell-specific targeting moieties forming a conjugate compoundfor efficient and specific delivery of the agent to a cell of interest.

[0022] The phrase “targeting moiety” means a molecule which serves todeliver the compound of the invention to a specific site for the desiredactivity. Targeting moieties include, for example, molecules thatspecifically bind molecules on a specific cell surface. Such targetingmoieties useful in the invention include anti-cell surface antigenantibodies. Cytokines, including interleukins and factors such asgranulocyte/macrophage stimulating factor (GMCSF) are also specifictargeting moieties, known to bind to specific cells expressing highlevels of their receptors.

[0023] The term “prodrug moiety” is a substitution group whichfacilitates use of a compound of the invention, for example byfacilitating entry of the drug into cells or administration of thecompound. The prodrug moiety may be cleaved from the compound, forexample by cleavage enzymes in vivo. Examples of prodrug moietiesinclude phosphate groups, peptide linkers, and sugars, which moietiescan be hydrolyzed in vivo.

[0024] “inhibit” means to reduce by a measurable amount, or to prevententirely.

[0025] “to treat” means to inhibit or block at least one symptom thatcharacterizes a pathologic condition, in a mammal threatened by, orafflicted with, the condition.

[0026] Compounds of the Invention

[0027] Compounds of the invention include quinazolines having theformula:

[0028] where:

[0029] R⁸ is iodo; (C₁-C₄)hydroxyalkyl, methylenedioxy, ethylenedioxy,benzyloxy, OCF₃. SCF₃, SO₃H, SO₂F, SO₂NR²R³ in which R² is hydrogen or(C₁-₄)alkyl and R³ is hydrogen, (C₁-C₄)alkyl, or phenyl, NR²R⁴ in whichR² is as defined above and R⁴ is phenyl, or R^(a) a group of the formula

[0030] in which R⁵ and R⁶ are each, independently, hydrogen,(C₁-C₄)alkyl or (C₁-C₄)perfluoroalkyl, and R⁷ is hydrogen, halo,hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)hydroxyalkyl, or N(R²)₂ inwhich R² is as defined above;

[0031] n is an integer of 1-4;

[0032] R^(b) is each, independently, hydrogen; halo; hydroxy; mercapto;(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)thioalkyl, (C₁-C₄)hydroxyalkyl,nitro, cyano, methylenedioxy, ethylenedioxy, COCH₃, CF₃, OCF₃; SCF₃;COOH; SO₃H; SO₂F; phenyl or phenyl substituted by a group selected fromhalo, hydroxy, mercapto, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)thioalkyl,(C₁-C₄)hydroxyalkyl, amino, nitro, cyano, CF₃, COOH, SO₃H, SO₂NR²R³ inwhich R² and R³ are as defined below, and SO₂F. R^(a) can also bebenzyloxy or benzyloxy substituted on the phenyl portion by a groupdefined above, NR²R³ in which R² is H or (C₁-C₄)alkyl and R³ is H,(C₁-C₄)alkyl, phenyl or phenyl substituted by a group as defined above;

[0033] R¹ is (C₁-C₄)alkyl, preferably methyl, or a pharmaceuticallyacceptable salt thereof, such as an acid addition salt.

[0034] Preferably, R^(a) is a member selected from the group consistingof I, NHC6H5, —OCH₂CH₂O—, —OCH₂O—, OCF₃, SCF₃, CH₂OH, C₂H40H, SO₃H,SO₂NH₂, and SO₂F; and ore preferably R^(a) is I OCF₃ or SO₂F. Mostpreferably, R^(a) is I or R^(a) is OCF₃.

[0035] In an alternative preferred compound, n is I and R^(a) is a groupof the formula:

[0036] Preferably, R⁵ and R⁶ are each, independently, H, CH₃ or CF₃, andmost preferably, R⁵ and R⁶ are CF₃ and R⁷ is NH₂.

[0037] In another preferred compound, R^(b) is at least one memberselected from the group consisting of F, Cl, Br, I, OH, NH₂, NO₂, CN,COOH, CH₃, and CF₃, and more preferably R^(b) is at least one memberselected from the group consisting of F, Cl, Br, OH, and CF₃.

[0038] Additional preferred quinazoline compounds useful in thetreatment of tumors are described more fully below and particularly inthe Examples. These include:

[0039] 4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline;

[0040] 4-(2′,4′,6′-tribromophenyl)amino-6,7-dimethoxyquinazoline;

[0041]4-(2′,3′,5′,6′-tetrafluoro-5′-bromophenyl)amino-6,7-dimethoxyquinazoline;

[0042] 4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline;

[0043] 4-(4′trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline; and

[0044]4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline.

[0045] Methods of Treatment

[0046] The compounds of the invention are useful for the treatment ofanimals, including humans. In particular, the compounds of the inventionhave been found to be potent inhibitors of tumor cell proliferation andsurvival, and effective to induce apoptosis of malignant cells.

[0047] Compounds of the invention have surprisingly been found to beeffective for inducing apoptosis and/or cytotoxicity of leukemia cells.In particular, 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazolinecompounds of the invention have been found to effectively induceapoptosis in multi-drug resistant leukemia. A preferred compound for thetreatment of multi-drug resistant leukemia is4-(3′-bromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline.

[0048] Compounds of the invention that are particularly useful fortreating leukemia include:

[0049] 4-(3′,5′-bromo-4-methylphenyl)amino-6,7-dimethoxyquinazoline,

[0050] 4-(2′,4′,6′-tribromophenyl)amino-6,7-dimethoxyquinazoline,

[0051]4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,

[0052] 4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,

[0053] 4-(3′-fluorophenyl)amino-6,7-dimethoxyquinazoline,

[0054] 4-(2′-fluorophenyl)amino-6,7-dimethoxyquinazoline,

[0055] 4-(4′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,

[0056] 4-(2′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline, and

[0057]4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline.

[0058] Compounds of the invention that are particularly useful fortreating breast tumors include:

[0059] 4-(3′-bromophenyl)amino-6,7-dimethoxyquinazoline,

[0060] 4-(3′,5′-dibromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,

[0061] 4-(3′-chloro-4′-hydroxyphenyl)amino-4,7-dimethoxyquinazoline,

[0062]4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,

[0063]4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,

[0064] 4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,

[0065] 4-(3′-fluorophenyl)amino-6,7-dimethoxyquinazoline, and

[0066] 4-(2′-fluorophenyl)amino-6,7-dimethoxyquinazoline.

[0067] Compositions

[0068] The compounds of the invention are useful as pharmaceuticalcompositions prepared with a therapeutically effective amount of acompound of claim 1 and a pharmaceutically acceptable carrier ordiluent.

[0069] The quinazoline compounds of the invention can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

[0070] Thus, quinazoline compounds of the invention may be systemicallyadministered, e.g., orally, in combination with a pharmaceuticallyacceptable vehicle such as an inert diluent or an assimilable ediblecarrier, or by inhalation or insufflation. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the quinazoline compounds may be combinedwith one or more excipients and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The quinazoline compounds may be combined with a fineinert powdered carrier and inhaled by the subject or insufflated. Suchcompositions and preparations should contain at least 0.1% quinazolinecompounds. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 2 to about 60%of the weight of a given unit dosage form. The amount of quinazolinecompounds in such therapeutically useful compositions is such that aneffective dosage level will be obtained.

[0071] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermnint, oil of wintergreen, or cherry flavoring maybe added. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, thequinazoline compounds may be incorporated into sustained-releasepreparations and devices.

[0072] The quinazoline compounds may also be administered intravenouslyor intraperitoneally by infusion or injection. Solutions of thequinazoline compounds can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol liquidpolyethylene glycols, triacetin and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

[0073] The pharmaceutical dosage forms suitable for injection orinfusion can include sterile aqueous solutions or dispersions or sterilepowders comprising the quinazoline compounds which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can to bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0074] Sterile injectable solutions are prepared by incorporating thequinazoline compounds in the required amount in the appropriate solventwith various of the other ingredients enumerated above, as required,followed by filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

[0075] For topical administration, the quinazoline compounds may beapplied in pure form, i.e., when they are liquids. However, it willgenerally be desirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0076] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Othersolid carriers include nontoxic polymeric nanoparticles ormicroparticles. Useful liquid carriers include water, alcohols orglycols or water-alcohol/glycol blends, in which the quinazolinecompounds can be dissolved or dispersed at effective levels, optionallywith the aid of non-toxic surfactants. Adjuvants such as fragrances andadditional antimicrobial agents can be added to optimize the propertiesfor a given use. The resultant liquid compositions can be applied fromabsorbent pads, used to impregnate bandages and other dressings, orsprayed onto the affected area using pumppe or aerosol sprayers.

[0077] Thickeners such as synthetic polymers, fatty acids, fatty acidsalts and esters, fatty alcohols, modified celluloses or modifiedmineral materials can also be employed with liquid carriers to formspreadable pastes, gels, ointments, soaps, and the like, for applicationdirectly to the skin of the user.

[0078] Examples of useful dermatological compositions which can be usedto deliver the quinazoline compounds to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) andWortztman (U.S. Pat. No. 4,820,508).

[0079] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0080] Generally, the concentration of the quinazoline compounds in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

[0081] The amount of the quinazoline compounds required for use intreatment will vary not only with the particular salt selected but alsowith the route of administration, the nature of the condition beingtreated and the age and condition of the patient and will be ultimatelyat the discretion of the attendant physician or clinician.

[0082] In general, however, a suitable dose will be in the range of fromabut 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg ofbody weight per day, such as 3 to about 50 mg per kilogram body weightof the recipient per day, preferably in the range of 6 to 90 mg/kg/day,most preferably in the range of 15 to 60 mg/kg/day.

[0083] The quinazoline compounds are conveniently administered in unitdosage form; for example, containing 5 to 1000 mg, conveniently 10 to750 mg, most conveniently, 50 to 500 mg of active ingredient per unitdosage form.

[0084] Ideally, the quinazoline compounds should be administered toachieve peak plasma concentrations of from about 0.5 to about 75 μM,preferably, about 1 to 50 μM, most preferably, about 2 to about 30 μM.This may be achieved, for example, by the intravenous injection of a0.05 to 5% solution of the quinazoline compounds, optionally in saline,or orally administered as a bolus containing about 1-100 mg of thequinazoline compounds. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the quinazolinecompounds.

[0085] The quinazoline compounds may conveniently be presented in asingle dose or as divided doses administered at appropriate intervals,for example, as two, three, four or more sub-doses per day. The sub-doseitself may be further divided, e.g., into a number of discrete looselyspaced administrations; such as multiple inhalations from an insulatoror by application of a plurality of drops into the eye.

[0086] Targeting Quinazolines to Cells

[0087] In a preferred embodiment, the quinazoline compound is targetedto cells where treatment is desired, for example, to leukemia cells, tobreast cells, or to other tumor cells. The compound is targeted to thedesired cell by conjugation to a targeting moiety that specificallybinds the desired cell, thereby directing administration of a conjugatedmolecule. Useful targeting moieties are ligands which specifically bindcell antigens or cell surface ligands, for example, antibodies againstthe B cell antigen, CD19 (such as B43) and the like.

[0088] To form the conjugates of the invention, targeting moieties arecovalently bonded to sites on the quinazoline compound. The targetingmoiety, which is often a polypeptide molecule, is bound to compounds ofthe invention at reactive sites, including NH₂, SH, CHO, COOH, and thelike. Specific linking agents are used to join the compounds. Preferredlinking agents are chosen according to the reactive site to which thetargeting moiety is to be attached.

[0089] Methods for selecting an appropriate linking agent and reactivesite for attachment of the targeting moiety to the compound of theinvention are known, and are described, for example, in Hermanson, etal., Bioconjugate Techniques, Academic Press, 1996; Hermanson, et al.,Immobilized Affinity Ligand Techniques, Academic Press, 1992; and PierceCatalog and Handbook, 1996, pp. T155-T201.

[0090] Administration of Quinazolines

[0091] According to the invention, quinazoline compounds may beadministered prophylactically, i.e., prior to onset the pathologicalcondition, or the quinazoline compounds may be administered after onsetof the reaction, or at both times.

EXAMPLES

[0092] The invention may be further clarified by reference to thefollowing Examples, which serve to exemplify some of the preferredembodiments, and not to limit the invention in any way.

Example 1 Synthesis of Quinazoline Derivatives

[0093] All chemicals were purchased from the Aldrich Chemical Company,Milwaukee, Wis., and were used directly for synthesis. Anhydroussolvents such as acetonitrile, methanol, ethanol, ethyl acetate,tetrahydrofuran, chloroform, and methylene chloride were obtained fromAldrich as sure seal bottles under nitrogen and were transferred toreaction vessels by cannulation. All reactions were carried out under anitrogen atmosphere.

[0094] The key starting material, 4-chloro-6,7-dimethoxyquinazoline, wasprepared according to published procedures (Nomoto, et al., 1990, Chem.Pharm. Bull., 38:1591-1595; Thomas, C. L., 1970, IN:Catalytic Processesand Proven Catalysts, Academic Press, New York, N.Y.) as outlined belowin Scheme 1. Specifically, 4,5-dimethoxy-2-nitrobenzoic acid(compound 1) was treated with thionyl chloride to form acid chloride,followed by reacting with ammonia to yield4,5-dimethoxy-2-nitrobenzamide (compound 2). Compound 2 was reduced withsodium borohydride in the presence of catalytic amounts of coppersulphate to give 4,5-dimethoxy-2-aminobenzamide (compound 3), which wasdirectly refluxed with formic acid to yield6,7-dimethoxyquinazoline-4(3H)-one (compound 4). Compound 4 was refluxedwith phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline(compound 5) in good yield.

[0095] Substituted quinazoline derivatives were prepared by thecondensation of 4-chloro-6,7-dimethoxyquinazoline with substitutedanilines as outlined below in Scheme 2:

[0096] Specifically, a mixture of 4-chloro-6,7-dimethoxyquinazoline (448mg, 2 mmols) and the substituted aniline (2.5 mmols) in EtOH (20 ml) washeated to reflux. After refluxing for 4-24 hours, an excess amount ofEt₃N was added, and the solvent was concentrated to give the crudeproduct which was recrystalized from DMF.

[0097] As discussed above, the novel hydroxy-substituted quinazolinederivatives of the invention were created by reacting the appropriatesubstituted anilines with the key starting material,4-chloro-6,7-dimethoxyquinazoline.

[0098] Physical Characteristics:

[0099] Melting points are uncorrected. ¹H NMR spectra were recordedusing a Varian Mercury 300 spectrometer in DMSO-d₆ or CDCl₃. Chemicalshifts are reported in parts per million (ppm) with tetramethylsilane(TMS) as an internal standard at zero ppm. Coupling constants (3) aregiven in hertz and the abbreviations s, d, t, q, and m refer to singlet,doublet, triplet, quartet and multiplet, respectively. Infrared spectrawere recorded on a Nicolet PROTEGE 460-IR spectrometer. Massspectroscopy data were recorded on a FINNIGAN MAT 95, VG 7070E-HF G.C.system with an HP 5973 Mass Selection Detector. UV spectra were recordedon BECKMAN DU 7400 and using MEOH as the solvent. TLC was performed on aprecoated silica gel plate (Silica Gel KGF; Whitman Inc). Silica gel(200-400 mesh, Whitman Inc.) was used for all column chromatographyseparations. All chemicals were reagent grade and were purchased fromAldrich Chemical Company (Milwaukee, Wis.) or Sigma Chemical Company(St. Louis, Mo.).

Example 2 Bromine Substituted Quinazoline Compounds

[0100] Bromine substituted quinazoline derivatives were synthesized andcharacterized as discussed above in Example 1. The structures andphysical data are shown below: Bromine Substituted Quinazoline CompoundsNo Name Structure Formula MW 1 P-79

C₁₆H₁₄BrN₃O₂ 360 2 P-88

C₁₇H₁₄BrN₃O₄ 404 3 P-97

C₁₆H₁₃Br₂N₃O₃ 455 4 P-111

C₁₇H₁₆BrN₃O₂ 374 5 P-112

C₁₆H₁₃Br₂N₃O₂ 439 6 P-154

C₁₆H₁₄BrN₃O₃ 376 7 P-160

C₂₃H₁₈BrN₃O₂ 448 8 P-164

C₁₇H₁₃BrN₂O₃ 373 9 P-190

C₁₇H₁₆BrN₃O₃ 389 10 P-210

C₁₇H₁₅Br₂N₃O₂ 453 11 P-211

C₁₇H₁₅Br₂N₃O₂ 453 12 P-212

C₁₇H₁₅Br₂N₃O₂ 453 13 P-214

C₁₆H₁₃BrFN₃O₂ 378 14 P-222

C₁₆H₁₂Br₃N₃O₂ 518 15 P-234

C₁₇H₁₇N₃O₂ 295 16 P-241

C₁₇H₁₅Br₂N₃O₂ 453 17 P-258

C₁₆H₁₅N₃O₂ 281 18 P-260

C₁₆H₁₄BrN₃O₂ 360 19 P-261

C₁₆H₁₄BrN₃O₂ 360 20 P-262

C₁₆H₁₃Br₂N₃O₂ 439 21 P-263

C₁₆H₁₃Br₂N₃O₂ 439 4-(3′-Bromophenyl)-amino-6,7-dimethoxyquinazoline(HI-P79) Yield 84.17%; m.p. 246.0-249.0° C. ¹H NMR(DMSO-d₆): δ 10.42(br,s, 1H, NH), 8.68(s, 1H, 2-H), 8.07-7.36(m, 5H, 5,2′,4′,5′,6′-H), 7.24(s,1H, 8H), 3.98(s, 3H, —OCH₃), 3.73(s, 3H, —OCH₃); IR(KBr)ν_(max): 3409,2836, 1632, 1512, 1443, 1243, 1068 cm⁻¹; GC/MS m/z 361(M⁺ + 1, 61.8),360(M⁺, 100.0), 359(M⁺ − 1, 63.5), 344(11.3), 222(10.9), 140(13.7).Anal. (C₁₆H₁₄BrN₃O₂HCl) C, H, N.4-(4′-Bromo-2′-caboxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P88)Yield 92.82%; m.p. > 300.0° C. ¹H NMR(DMSO-d₆ + CF₃CO₂H): δ 9.95(d, 1H),8.74(d, 1H, Ar—H), 8.30, 8.28(2d, 2H), 7.95(d, 1H), 7.83(s, 1H), 4.21(s,3H, —OCH₃), 4.15(s, 3H, —OCH₃). UV(MeOH): 205, 229.0 nm. IR(KBr)ν_(max):3444(br), 2737, 1592, 1504, 1443, 1273, 1070 cm⁻¹. GC/MS m/z 388(M⁺ + 1—OH, 18.08), 387(M⁺ —OH, 100.00), 386(M⁺ − 1 —OH, 30.84), 385(97.52),299(4.78). Anal. (C₁₆H₁₄BrN₃O₂HCl) C, H, N.4-(3′,5′-Dibromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P97). Yield 72.80%; m.p. > 300.0° C. ¹H NMR(DMSO-d₆): δ 9.71(s, 1H,—NH), 9.39(s, 1H, —OH), 8.48(s, 1H, 2-H), 8.07(s, 2H, 2′,6′-H), 7.76(s,1H, 5-H), 7.17(s, 1H, 8-H), 3.94(s, 3H, —OCH₃), 3.91(s, 3H, —OCH₃).UV(MeOH): 208.0, 210.0, 245.0, 320.0 nm; IR(KBr)ν_(max): 3504(br), 3419,2868, 1627, 1512, 1425, 1250, 1155 cm⁻¹; GC/MS m/z 456(M⁺ + 1, 54.40),455(M⁺, 100.00), 454(M⁺ − 1, 78.01), 439(M⁺ —OH, 7.96), 376(M⁺ + 1 —Br,9.76), 375(M⁺ —Br, 10.91), 360(5.23). Anal. (C₁₆H₁₃Br₂N₃O₃) C, H, N.4-(3′-Bromo-4′-methylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P111):Yield 82.22%; m.p. 225.0-228° C. ¹H NMR(DMSO-d₆): δ 10.23(s, 1H, —NH),8.62(s, 1H, 2-H), 8.06(d, 1H, J_(2′,6′)=2.1 Hz, 2′-H), 7.89(s, 1H, 5-H),7.71(dd, 1H, J_(5′,6′)=8.7 Hz, J_(2′,6′)=2.1 Hz, 6′-H), 7.37(d, 1H,J_(5′,6′)=8.7 Hz, 5′-H), 7.21(s, 1H, 8-H), 3.96(s, 3H, —OCH₃), 3.93(s,3H, —OCH₃). UV(MeOH): 204.0, 228.0, 255.0, 320.0 nm. IR(KBr)ν_(max):3431, 3248, 2835, 1633, 1517, 1441, 1281, 1155 cm⁻¹. GC/MS m/z 375(M⁺ +1, 76.76), 374(M⁺, 100.00), 373(M⁺ − 1, 76.91), 358(M⁺ + 1 —OH, 11.15),357(1.42), 356(6.31). Anal. (C₁₇H₁₆BrN₃O₂.HCl) C, H, N.4-(2′,5′-Dibromophenyl)-amino-6,7-dimethoxyquinazoline (HI-P112): Yield70.05%; m.p. > 300.0° C. ¹H NMR(DMSO-d₆): δ 11.51(s, 1H, —NH), 8.76(s,1H, 2-H), 8.21(s, 1H, 5-H), 7.81(d, 1H, J_(4′,6′)=2.4 Hz, 6′-H), 7.75(d,1H, J_(3′,4′)=8.7 Hz, 3′-H), 7.55(dd, 1H, J_(4′,6′)=2.4 Hz,J_(3′,4′)=8.7 Hz, 4′-H), 7.33(s, 1H, 8-H), 3.98(s, 3H, —OCH₃), 3.97(s,3H, —OCH₃). UV(MeOH): 208.0, 238.0, 330.0 nm. IR(KBr)ν_(max): 3444,2836, 1628, 1510, 1431, 1277, 1070 cm⁻¹. GC/MS m/z 440(M⁺ + 1, 10.12),439(M⁺, 7.0), 438(M⁺ − 1, 3.63), 360(M⁺ + 1 —Br, 99.42), 359(M⁺ —Br,20.45), 358(M⁺ − 1 —Br, 100.00), 343(20.80), 299(8.62). Anal.(C₁₆H₁₃Br₂N₃O₂.HCl) C, H, N.4-[(3′-Bromo-9′-fluorenone)-2′]-amino-6,7-dimethoxyquinazoline(HI-P119): Yield 75.23%; m.p. 255.0-257.0° C. ¹H NMR(DMSO-d₆): δ 8.77(s,1H, —NH), 8.33(s, 1H, 2-H). 7.89(s, 1H, 5-H), 7.40(s, 1H, 8-H),7.74-7.26(m, 6H, Ar—H), 4.12(s, 3H, —OCH₃), 4.11(s, 3H, —OCH₃).UV(MeOH): 205, 229.0, 251.0, 320.0 nm. IR(KBr)ν_(max): 3444, 2836, 1628,1510, 1431, 1277, 1070 cm⁻¹. GC/MS m/z 464(M⁺ + 2, 40.81), 463(M⁺ + 1,7.56), 462(M⁺, 27.26), 384(M⁺ + 2 —Br, 69.56), 383(M⁺ + 1 —Br, 35.50),382(M⁺ —Br, 100.00), 352(10.85), 206(26.73), 191(11.31). Anal.(C₂₃H₁₆BrN₃O₃HCl) C, H, N.4-(2′,3′,5′,6′-Tetrafluoro-4′-bromolphenyl)amino-6,7-dime-thoxyquinazoline(HI-P144: Yield 78.24%; m.p. 180.0-182.0° C. ¹H NMR(DMSO-d₆): δ 7.78(s,1H, 2-H), 7.53(s, 1H, 5-H), 6.79(s, 1H, 8-H), 3.81(s, 3H, —OCH₃),3.3.79(s, 3H, —OCH₃). Anal(C₁₆H₁₀BrF₄N₃O₂.HCl) C, H, N.4-(3′-Bromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P154):Yield 89.90%; m.p. 233.0-233.5° C. ¹H NMR(DMSO-d₆): δ 10.08(s, 1H, —NH),9.38(s, 1H, —OH), 8.40(s, 1H, 2-H), 7.89(d, 1H, J_(2′,6′)=2.7 Hz, 2′-H),7.75(s, 1H, 5-H), 7.55(dd, 1H, J_(5′,6′)=9.0 Hz, J_(2′,6′)=2.7 Hz,6′-H), 7.14(s, 1H, 8-H), 6.97(d, 1H, J_(5′,6′)=9.0 Hz, 5′-H), 3.92(s,3H, —OCH₃), 3.90(s, 3H, —OCH₃). UV(MeOH): 203.0, 222.0, 250.0, 335.0 nm.IR(KBr)ν_(max): 3431(br), 2841, 1624, 1498, 1423, 1244 cm⁻¹. GC/MS m/z378(M⁺ + 2, 90.68), 377(M⁺ + 1, 37.49), 376(M⁺, 100.00), 360(M⁺, 3.63),298(18.86), 282(6.65). Anal. (C₁₆H₁₄BrN₃O₃.HCl) C, H, N.4-[(7′-Bromofluorene)-2′]-amino-6,7-dimethoxyquinazoline (HI-P160):Yield 73.21%; m.p. 254.0-256.0° C. ¹H NMR(DMSO-d₆): δ 9.69(br, s, 1H,—NH), 8.52(s, 1H, 2-H), 8.12-7.20(m, 9H, 5, 8, 1′, 3′, 4′, 5′, 6′, 8′,9′-H), 3.99(s, 3H, —OCH₃), 3.94(s, 3H, —OCH₃). UV(MeOH): 208.0, 223.0,348.0 nm. IR(KBr)ν_(max): 3421, 2820, 1624, 1516, 1431, 1294, 1223 cm⁻¹.GC/MS m/z 450(M⁺ + 2, 100), 449(M⁺ + 1, 35), 448(M⁺, 95), 311(25). Anal.(C₂₃H₁₈BrN₃O₂.HCl) C, H, N. 4-(3′-Bromobenzoyl)-6,7-dimethoxyquinazoline(HI-P164). Yield 81.20%, m.p. 258.0-263.0° C. ¹H NMR(DMSO-d₆): δ 9.25(s,1H, 2-H), 8.14(s, 1H, 5-H), 7.92-7.43(m, 4H, 2′,4′,5′,6′-H), 7.40(s, 1H,8-H), 4.11(s, 3H, —OCH₃), 4.00(s, 3H, —OCH₃). UV(MeOH): 203.0, 220.0,238.0 nm. IR(KBr)ν_(max): 3432, 1664, 1504, 1431, 1230 cm⁻¹. GC/MS m/z374(M⁺ + 1, 48.96), 373(M⁺, 34.93), 372(M⁺ − 1, 47.67), 357(58.74),343(100.00), 293(M⁺ —Br, 31.48), 189(26.27). Anal. (C₁₇H₁₃BrN₂O₃) C, H,Br, N.4-(4′-Bromo-6′-hydroxymethylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P190): Yield 73.08%; m.p. 222.0-223.0° C. ¹H NMR(DMSO-d₆): δ11.30(s, 1H, —OH), 8.22(s, 1H, —NH), 7.77-7.23(m, 5H, 5,8,2′,3′,5′-H),4.49(s, 2H, PhCH₂—H), 4.01(s, 3H, —OCH₃), 3.90(s, 3H, —OCH₃). UV(MeOH):207.0, 250.0, 332.0 nm. IR(KBr)ν_(max): 3446, 2829, 2752, 1652, 1560,1471, 1365, 1280 cm⁻¹. GC/MS m/z 391(M⁺ + 1, 29.33), 389(M⁺, 29.82),360(M⁺ —CH₂OH, 50.76), 358(52.39), 311(18.33), 280(43.20), 206(62.80),191(100.00). Anal. (C₁₇H₁₆BrN₃O₃.HCl) C, H, N.4-(2′,3′-Dibromo-4′-methylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P210): Yield 81.24%, mp 233.0-236.0° C., ¹H NMR(DMSO-d₆): δ 8.55(s,1H, —NH), 8.08(s, 1H, 2-H), 7.33-7.17(m, 4H, 5,8,5′,6′-H), 3.89(s, 6H,—OCH₃), 2.35(s, 3H, —CH₃). UV(MeOH): 207.0, 232.0, 247.0, 330.0 nm.IR(KBr)ν_(max): 3448, 2840, 1629, 1580, 1525, 1420, 1281 cm⁻¹. GC/MS m/z454(M⁺ + 1, 4.45) , 453(M⁺, 11.31), 452(M⁺ − 1, 4.45), 375(20.36),374(97.59), 373( 23.55), 372(100.00), 358(19.61), 356(18.43). Anal.(C₁₇H₁₅Br₂N₃O₂.HCl) C, H, N.4-(2′,5′-Dibromo-4′-methylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P211): Yield 83.50%; m.p. 282.0-284.0° C. ¹H NMR(DMSO-d₆): δ11.30(s, 1H, —NH), 8.58(s, 1H, 2-H), 8.00(s, 1H, 5-H), 7.65(s, 1H,6′-H), 7.60(s, 1H, 3′-H), 7.13(s, 1H, 8-H), 3.79(s, 3H, —OCH₃), 3.78(s,3H, —OCH₃), 2.29(s, 3H, —CH₃). UV(MeOH): 207.0, 239.0, 330.0 nm.IR(KBr)ν_(max): 3442, 2620, 1631, 1580, 1514, 1380, 1280 cm⁻¹. GC/MS m/z454(M⁺ + 1, 5.86), 453(M⁺, 16.16), 452(M⁺ − 1, 5.35), 374(92.12),373(23.66), 372(100.00), 358(17.68), 356(17.35). Anal.(C₁₇H₁₅Br₂N₃O₂.HCl) C, H, N.4-(3′,5′-Dibromo-4′-methylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P212): Yield 83.47%; m.p. 275.0-279.0° C. ¹H NMR(DMSO-d₆): δ11.30(s, 1H, —NH), 8.58(s, 1H, 2-H), 8.35(s, 1H, 5-H), 7.24(s, 2H,2′,6′-H), 7.13(s, 1H, 8-H), 3.91(s, 3H, —OCH₃), 3.88(s, 3H, —OCH₃),2.31(s, 3H, —CH₃). UV(MeOH): 237.0, 307.0, 319.0 nm. IR(KBr)ν_(max):3471, 3434, 2640, 1633, 1580, 1504, 1420, 1281 cm⁻¹. GC/MS m/z 454(M⁺ +1, 5.34), 453(M⁺, 16.05), 452(M⁺ − 1, 5.87), 374(99.02), 373(26.20),372(100.00), 358(20.39), 356(19.98), 32(8.29), 314(8.49), 206(19.02).Anal. (C₁₇H₁₅Br₂N₃O₂HCl) C, H, N.4-(2′-Fluoro-4′-bromophenyl)-amino-6,7-dimethoxyquinazoline (HI-P214):Yield 77.21%; m.p. 243.0-245.0° C. ¹H NMR(DMSO-d₆): δ 8.57(s, 1H, 2-H),7.91(s, 1H, 5-H), 7.57(d, 1H, 3′-H), 7.34(m, 2H, 5′,6′-H), 7.07(s, 1H,8-H), 3.78(s, 3H, —OCH₃), 3.77(s, 3H, —OCH₃). UV(MeOH): 204.0, 215.0,250.0, 330.0 nm. IR(KBr)ν_(max): 3431, 2629, 1633, 1580, 1511, 1420,1278 cm⁻¹. GC/MS m/z 379(M⁺ + 1, 34.39), 378(M⁺, 21.33), 377(M⁺ − 1,39.08), 360(62.05), 359(31.58), 358(62.57), 357(19.81), 299(19.31),298(100.00), 282(17.88), 240(28.76). Anal. (C₁₆H₁₃BrFN₃O₂HCl) C, H, N.4-(2′,4′,6′-Tribromophenyl)amino-6,7-dimethoxyquinazoline (HI-P222):Yield 54.86%; m.p. 250.0-255.0° C. ¹H NMR(DMSO-d₆): δ 8.00(s, 1H, 2-H),7.89(s, 2H, 3′, 5′-H), 7.74(s, 1H, 5-H), 7.01(s, 1H, 8-H), 3.87(s, 3H,—OCH₃), 3.86(s, 3H, —OCH₃). UV(MeOH): 209.0, 236.0, 333.0 nm.IR(KBr)ν_(max): 3417, 2838, 1625, 1514, 1429, 1276, 1073 cm⁻¹. GC/MS m/z519(M⁺ + 1, 18.12), 518(M⁺, 17.30), 517(M⁺ − 1, 16.63), 439(M⁺ + 1-Br,99.42), 438(M⁺ − Br, 95.45), 437(M⁺ − 1 —Br, 100.00), 359(20.80),358(18.62), 357(19.32), 281(88.98), 207(15.42). Anal. (C₁₆H₁₂Br₃N₃O₂HCl)C, H, N.4-(2′,6′-Dibromo-4′-methylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P241): Yield 79.47%, m.p. 235.0-237.0° C. ¹H NMR(DMSO-d₆): δ 9.77(s,1H, —HN), 8.20(s, 1H, 2-H), 7.87(s, 1H, 8-H), 7.61(s, 2H, 3′,5′-H),7.15(s, 1H, 5-H), 3.93(s, 6H, —OCH₃). UV(MeOH): 208.0, 245.0, 318.0,339.0 nm. IR(KBr)ν_(max): 3241, 2839, 2783, 1635, 1580, 1514, 1420,1360, 1281 cm⁻¹. GC/MS m/z 454(M⁺ + 1, 7.86), 453(M⁺, 56.16), 452(M⁺ −1, 15.30), 374(95.12), 373(18.66), 372(100.00), 358(29.64), 356(19.36).Anal. (C₁₇H₁₅Br₂N₃O₂HCl) C, H, N.4-(4′-Bromophenyl)-amino-6,7-dimethoxyquinazoline (HI-P260): Yield75.28%. m.p. 270.0-272.0° C. ¹H NMR(DMSO-d₆): δ 11.30(s, 1H, —NH),8.85(s, 1H, 2-H), 8.27(s, 1H, 5-H), 7.70(s, 4H, 2′,3′,5′,6′-H), 7.32(s,1H, 8H), 4.02(s, 3H, —OCH₃). 4.00(s, 3H, —OCH₃). UV(MeOH): 204.0, 218.0,252.0, 335.0 nm. IR(KBr)ν_(max): 3431, 3034, 2636, 1635, 1589, 1514,1435, 1284 cm⁻¹. GC/MS m/z 361(M⁺ + 1, 74.00), 360(M⁺, 100.00), 359(M⁺ −1, 72.00), 358(M⁺ − 2, 95.00), 329(3.20), 301(13.0), 281(21.0),207(38.0). Anal. (C₁₆H₁₄BrN₃O₂.HCl) C, H, N.4-(2′-Bromophenyl)-amino-6,7-dimethoxyquinazoline (HI-P261): Yield71.94%; m.p. 241.0-243.0° C. ¹H NMR(DMSO-d₆) δ 11.67(d, 1H, —NH),8.79(s, 1H, 2-H), 8.32(s, 1H, 5-H), 7.86-7.38(m, 4H, 3′,4′,5′,6′-H),7.40(s, 1H, 8H), 4.01(s, 6H, —OCH₃). UV(MeOH): 204.0, 226.0, 248.0,330.0 nm. IR(KBr)ν_(max) : 3454, 3032, 2638, 1630, 1589, 1514, 1430,1281 cm⁻¹. GC/MS m/z 361(M⁺ + 1, 7.00), 360(M⁺, 5.00), 359(M⁺ − 1,6.00), 358(M⁺ − 2, 5.00), 301(13.0), 281(21.0), 280(100.00), 207(25.00).Anal (C₁₆H₁₄BrN₃O₂.HCl) C, H, N.4-(2′,6′-Dibromophenyl)-amino-6,7-dimethoxyquinazoline (HI-P262): Yield69.45%, mp 243.0-246.0° C., ¹H NMR(DMSO-d₆): δ 11.91(d, 1H, —NH),8.80(s, 1H, 2-H), 8.43(s, 1H, 5-H), 7.86(d, 2H, J=8.4 Hz, 3′,5′-H),7.49(s, 1H, 8H), 7.35(t, 1H, J=8.4 Hz, 4′-H), 4.02(s, 3H, —OCH₃),4.01(s, 3H, —OCH₃). UV(MeOH): 208.0, 227.0, 245.0, 330.0 nm.IR(KBr)ν_(max): 3454, 3032, 2638, 1630, 1589, 1514, 1430, 1281 cm⁻¹.4-(2′,4′-Dibromophenyl)-amino-6,7-dimethoxyquinazoline (HI-P263): Yield70.62%; m.p. 257.0-262.0° C. ¹H NMR(DMSO-d₆): δ 11.91(d, 1H, —NH),8.79(s, 1H, 2-H), 8.21(s, 1H, 5-H), 8.12-7.51(m, 3H, 3′,5′,6′-H),7.35(s, 1H, 8-H), 4.01(s, 3H, —OCH₃), 3.99(s, 3H, —OCH₃). UV(MeOH):208.0, 210.0, 248.0, 330.0 nm. IR(KBr)ν_(max): 3458, 3028, 2641, 1633,1594, 1511, 1435, 1277 cm⁻¹.

Example 3

[0101] Chlorine Substituted Quinazoline Compounds Chlorine substitutedquinazoline derivatives were synthesized and characterized as discussedabove in Example 1. The structures and physical data are shown below: NoName Structure Formula MW 1 P-87

C₁₆H₁₄ClN₃O₂ 316 2 P-93

C₁₆H₁₄ClN₃O₃ 331 3 P-189

C₁₆H₁₃Cl₂N₃O₃ 365 4 P-197

C₁₆H₁₄ClN₃O₃ 331 5 P-268

C₁₆H₁₄ClN₃O₂ 316 6 P-269

C₁₆H₁₄ClN₃O₂ 316 7 P-278

C₁₆H₁₄ClN₃O₃ 331 8 P-415

C₂₀H₁₆ClN₃O₂ 365 4-(3′-Chlorophenyl)-amino-6,7-dimethoxyquinazoline(HI-P87). Yield 76.98%; m.p. 242.0-245.0° C. ¹H NMR(DMSO-d₆): δ10.47(br, s, 1H, NH), 8.69(s, 1H, 2-H), 8.06(s, 1H, 5-H), 7.95-7.23(m,4H, 2′,4′,5′,6′-H), 7.24(s, 1H, 8-H), 3.98(s, eH, —OCH₃), 3.35(s, 3H,0OCH₃). UV(MeOH): 228.0, 251.0, 332.0 nm. IR(KBr)ν_(max): 3406, 2839,1632, 1516, 1443, 1278, 1068 cm⁻¹. GC/MS m/z 316(M⁺ − 1, 68.34), 314(M⁺− 2, 100.00, 344(11.34), 222(4.35), 140(9.86). Found: C, 54.62; H, 4.68;N, 11.93; Cl, 19.23. C₁₆H₁₄ClN₃O₂.HCl requires: C, 54.70; H, 4.28; N,11.96; Cl, 19.96%.4-(c′-Chloroo-6′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (HI-P93)Yield 83.08%; m.p. 295.0° C.(dec). ¹H NMR9DMSO-d₆: δ 10.14(s, 1H, —OH),8.37(s, 1H, 2-H), 7.78(s, 1H, 5H), 7.57(d, 1H, J_(2′,4′)=2.4 Hz, 2′-H),), 7.16(s, 1H, 8-H), 7.07(dd, 1H, J_(2′,4′)=2.4 Hz, J_(4′,5′)=8.7 Hz,4′-H), 6.92(d, 1H, J_(4′,5′)=8.7 Hz, 5′-H), 3.93(s, 3H, —OCH₃). 3.92(s,3H, —OCH₃). UV(MeOH): 205, 229.0, 251.0, 320.0 nm. IR(KBr)ν_(max):3500(br), 3430, 2835, 1622, 1512, 1432, 1259 cm⁻¹. GC/MS m/z 333(M⁺ + 2,13.41), 332(M⁺ + 1, 9.73, 331(M⁺, 39.47), 314(M⁺ —OH, 100.00),298(7.64). Found: C, 52.25; H, 4.07; N, 11.39. C₁₆H₁₄ClN₃O₃.HClrequires: C, 52.32; H, 4.09; N, 11.44%.4-(4′-Hydroxyl-3′,5′-dichlorophenyl)amino-6,7-dimethoxyquinazoline(HI-P189) Yield 79.45%; m.p. 293.0-295.0° C. ¹H NMR-DMSO-d₆): δ 11.32(s,1H, —NH), 10.34(s, 1H, —OH), 8.87(s, 1H, 2-H), 8.29(s, 1H, 5-H), 7.90(s,2H, 2′,6′-H), 7.32(s, 1H, 8-H), 4.01(s, 3H, —OCH₃), 3.99(s, 3H, —OCH₃).UV(MeOH): 213.0, 232.0, 250.0, 335.0 nm. IR(KBr)ν_(max): 3479, 2564,1641, 1579, 1429, 1282, 1147 cm⁻¹. GC/MS m/z 367(M⁺ = 2, 66.57),366(M⁺=1, 75.91), 365(M⁺, 100.00), 364(M⁺ − 194.08), 349(M⁺ —OH, 11.16).Anal. (C₁₆H₁₃Cl₂N₃O₃) C, H, N. Found: C, 48.93; H, 4.51; N, 10.00.C_(17o)H₁₇Cl₂N₃O₃.Hcl requires: C, 48.80; H, 4.31; N, 10.04.%.4-(3′-Chloro-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P197). Yield 84.14%; m.p. 245.0° C.(dec). ¹H NMR(DMSO-d₆): δ10.00(s, 1H, —NH), 9.37(s, 1H, —OH), 8.41(s, 1H, 2-H), 7.78(s, 1H, 5-H),7.49(d, 1H, J_(2′,5′)=2.7 Hz, 2′-H), 7.55(dd, 1H, J_(5′,6′)=9.0 Hz,J_(2′,6′)=2.7 Hz, 6′-H), 7.16(s, 1H, 8-H), 6.97(d, 1H, J_(5′,6′)=9.0 Hz,5′H), 3.93(s, 3H, —OCH₃), 3.91(s, 3H, —OCH₃). UV(MeOH): 209.0, 224.0,249.0, 330.0 nm. IR(KBr)ν_(max): 3448, 2842, 1623, 1506, 1423, 1241cm⁻¹. GC/MX m/z: 341(M⁺, 100.00), 326(M⁺ —CH₃, 98.50), 310(M⁺ —OCH₃,12.5), 295(9.0.), 189(13.5), 155(13.8). Found: C, 521.35; H, 4.16; Cl,19.15; N, 11.39. C₁₆H₁₄ClN₃O₃.HCl requires: C, 52.32; H, 4.09; Cl,19.07; N, 11.44%. 4-(2′-Chlorophenyl)-amino-6,7-dimethoxyquinazoline(HI-P268) Yield 87.28%; m.p. 247.0-279.5° C. ¹H NMR(DMSO-d₆): δ 11.71(s,1H, —NH), 8.78(s, 1H, 2-H), 8.33(s, 1H, 5-H), 7.67(s, 1H, 8H),7.68-7.42(m, 4H, 3′,4,5,6′-H), 4.00(s, 3H, —OCH₃), 3.99(s, 3H, —OCH₃).UV(MeOH): 213.0, 234.0, 251.0, 331.0 nm. IR(KBr)ν_(max): 3479, 2566,1643, 1577, 1429, 1282, 1147 cm⁻¹. GC/MX m/z 317(M⁺ + 1, 6.60), 316(M⁺,6.60), 315(M⁺ − 1, 18.52), 314(M⁺ − 2, 11.11), 281(21.22), 280(M⁺ —Cl,100.00), 264(29.62). Found: C, 54.51; H, 4.41; N, 11.81.C₁₆H₁₄ClN₃O₂.HCl requires: C, 54.45; H, 4.26; N, 11.93%.4-(4′-Chlorophenyl)-amino-6,7-dimethoxyquinazoline (HI-P269) Yield94.94%. m.p. 248.0-250.0° C. ¹H NMR(DMSO-d₆): δ 11.62(s, 1H, —NH),8.85(s, 1H, 2-H), 8.42(s, 1H, 5-H), 7.88(d, 2H, J=8.7 Hz, 3′, 5′, —H),7.54(d, 2H, J=8.7 Hz, 2′, 6′, —H), 7.38(s, 1H, 8-H0, 4.02(s, 3H, —OCH₃),3.99(s, 3H, —OCH₃). UV(MeOH): 215.0, 230.0, 253.0, mn. IR(KBr)ν_(max):3477, 2563, 1640, 1578 cm⁻¹. GC/MX m/z 317(M⁺ + 1, 18.18), 316(M⁺,29.55), 315(M⁺ − 1, 48.85), 314(M⁺ − 2, 61.36), 281(32., 95),207(100.00). Found: C, 54.65; H, 4.38; N, 11.92. C₁₆H₁₄ClN₃O₂.HClrequires: C, 54.55; H, 4.26; N, 11.93%.4-(4′-Hydroxyl-2′-chlorophenyl)-amino-6,7-dimethoxy-quinazoline(HI-P278) Yield 81.44%; m.p. 245.0-247.0° C. ¹H NMR(DMSO-d₆): δ 11.39(s,1H, —NH), 10.30(s, 1H, —OH), 8.75(s, 1H, 2-H), 8.24(s, 1H, 5-H),7.38-6.85(m, 3H, 3′,5′,6′-H), 7.37(s, 1H, 8H), 3.98(s, 3H, —OCH₃),3.96(s, 3H, —OCH₃). UV(MeOH): 222.0, 234.0, 239.0, 245.0, 254.0, 348.0nm. IR(KBr)ν_(max): 3448, 3242, 3144, 3025, 2917, 2834, 1638, 1591,1514, 1437, 1365, 1277, 1209 cm⁻¹. GC/MS m/z: 332(M⁺ + 1, 5.00), 331(M⁺,17.00), 330(M⁺ − 1, 5.00), 297(17.00), 296(100.00), 281(18.00),280(29.00), 253(9.00). Found: C, 52.17; 11, 4.06; N, 11.32.C₁₆H₁₄ClN₃O₃.HCl requires: C, 52.32; H, 4.01; N, 11.44%.4-(4′-Chloronaphthy-1′)-amino-6,7-dimethoxyquinazoline (HI-P415) Yield,85.07%. m.p. 245.0-248.0° C. ¹H NMR(DMSO-d₆): δ 11.91(s, 1H, —NH),8.66(s, 1H, 2-H), 8.45(s, 1H, 5-H), 8.30-7.62(m, 6H,2′,3′,5′,6′,7′,8′-H), 7.38(s, 1H, 8-H), 4.03(s, 3H, —OCH₃), 4.01(s, 3H,—OCH₃). UV(MeOH): 211.0, 233.0, 250.0, mn. IR(KBr)ν_(max): 3481, 2567,1645, 1579 cm⁻¹. Found: C, 59.32; H, 4.27; N, 10.24. C₂₀H₁₆ClN₃O₂.HClrequires: C, 59.70; 11, 4.23; N, 10.48%.

Example 4 Iodine Substituted Quinazoline Compounds

[0102] Iodine substituted quinazoline derivatives were synthesized asdiscussed above in Example 1, and analyzed. The structures and physicaldata are shown below: Iodine Substituted Quinazoline Compounds No NameStructure Formula MW 1 P-270

C₁₆H₁₄IN₃O₂ 407 2 P-271

C₁₆H₁₄IN₃O₂ 407 3 P-300

C₁₆H₁₄IN₃O₂ 407 4 P-294

C₁₆H₁₃I₂N₃O₃ 549 5 P-299

C₁₆H₁₄IN₃O₃ 423 4-(2′-Iodophenyl)-amino-6,7-dimethoxyquinazoline(P-270): Yield 75.37%; m.p. 225.0-230.0° C. ¹H NMR(DMSO-d₆): δ 11.74(s,1H, —NH), 8.79(s, 1H, 2-H), 8.33(s, 1H, 5-H), 8.05-7.13(m, 4H,3′,4,5,6′-H), 7.44(s, 1H, 8H), 4.01(s, 6H, —OCH₃). UV(MeOH): 219.0,222.0, 253.0, 342.0 nm. IR(KBr)ν_(max): 3165, 3027, 2827, 1639, 1572,1501, 1434, 1275, 1070 cm⁻¹. GC/MS m/z 408(M⁺ + 1, 3.47), 407(M⁺,15.28), 406(M⁺ − 1, 3.47), 281(33.33), 280(M⁺ —I, 100.00), 264(50.00),207(34.72). Found: C, 43.62; H, 3.60; N, 9.42. C₁₆H₁₄IN₃O₂.HCl requires:C, 43.34; H, 3.38; N, 9.48%.4-(3′-Iodophenyl)-amino-6,7-dimethoxyquinazoline (HI-P271): Yield79.85%; m.p. 235.0-242.0° C. ¹H NMR(DMSO-d₆): δ 11.43(s, 1H, —NH),8.88(s, 1H, 2-H), 8.33(s, 1H, 5-H), 8.13(s, 1H, 2′-H), 7.80-7.26(m, 3H,4′,5′,6′-H), 7.35(s, 1H, 8H), 4.02(s, 3H, —OCH₃), 4.00(s, 3H, —OCH₃).UV(MeOH): 203.0, 210.0, 228.0, 251.0, 331.0 nm. (KBr)ν_(max): 3191,3022, 2940, 2836, 2576, 1629, 1516, 1444, 1276, 1153, 1060 cm¹. GC/MSm/z 406(M⁺, 1.52), 405(M⁺ − 1, 6.22), 281(35.33), 207(100.00). Found: C,43.55; H, 3.43; N, 9.32. C₁₆H₁₄IN₃O₂.HCl requires: C, 43.34; H, 3.38; N,9.48%. 4-(4′-Hydroxy-3,5-diiodophenyl)-amino-6,7-dimethoxy-quinazoline(HI-P294: Yield 77.47%; m.p. 259.0-260.0° C. ¹H NMR(DMSO-d₆): δ 11.13(s,1H, NH), 9.73(s, 1H, —OH), 8.87(s, 1H, 2-H), 8.16(s, 1H, 5-H), 8.09(s,2H, 2′,6′-H), 7.28(s, 1H, 8H), 3.98(s, 6H, —OCH₃). UV(MeOH)λ_(max) (ε):.217.0, 227.0, 252.0 nm. IR(KBr)ν_(max): 3457, 3201, 2934, 2832, 2566,1629, 1562, 1521, 1439, 1275, 1075 cm⁻¹. GC/MS m/z: 422(M⁺ —I, 33.53),405(7.50), 281(86.67), 221(51.80), 207(91.30). Found: C, 32.60; H, 2.50;N, 6.92. C₁₆H₁₃I₂N₃O₃.HCl requires: C, 32.82; H, 2.39; N, 7.18%.4-(4′-Hydroxy-3′-iodophenyl)-amino-6,7-dimethoxyquinazoline (HI-P299)Yield 71.59%; m.p. 248.0-250.0° C. ¹H NMR(DMSO-d₆): δ 11.32(d, 1H, NH),10.62(s, 1H, —OH, 8.79(s, 1H, 2-H), 8.26(s, 1H, 5-H), 7.98-6.98(m, 3H,2′,3′,6′-H), 7.32(s, 1H, 8H), 3.98(s, 3H, —OCH₃), 3.97(s, 3H, —OCH₃).UV(MeOH)λ_(max) (ε): 217.0 , 227.0, 252.0 nm. IR(KBr)ν_(max): 3411,2975, 2730, 2366, 1634, 1573, 1501, 1429, 1229, 1075 cm⁻¹. GC/MS m/z:406(M⁺ − 1, 3.33), 405(M⁺ − 2, 7.50), 281(M⁺ − 1 —I, 26.67), 253(11.80),207(100.00). Found: C, 41.96; H, 3.40; N, 8.98. C₁₆H₁₄IN₃O₃.HClrequires: C, 41.83; H, 3.26; N, 9.15%.4-(4′-Iodophenyl)-amino-6,7-dimethoxyquinazoline (HI-P300): Yield85.24%; m.p. 240.0-242.0° C. ¹H NMR(DMSO-d₆): δ 11.51(s, 1H, NH),8.82(s, 1H, 2-H), 8.37(s, 1H, 5-H), 7.81(d, 2H, J=8.4 Hz, 2′,6′-H),7.55(d, 2H, J=8.4 Hz, 3′,5′-H), 7.35(s, 1H, 8H), 4.01(s, 3H, —OCH₃),3.98(s, 3H, —OCH₃). UV(MeOH): 217.0, 227.0, 252.0 nm. IR(KBr)ν_(max):3211, 3032, 2832, 2720, 1629, 1573, 1501, 1434, 1235, 1153, 1070 cm⁻¹.GC/MS m/z 406(M⁺ − 1, 3.33), 405(M⁺ − 2, 7.50), 281(M⁺ − 1 —I, 26.67),253(11.80), 207(100.00). Found: C, 43.40; H, 3.39; N, 9.36.C₁₆H₁₄IN₃O₂.HCl. requires: C, 43.34; H, 3.38; N, 9.48%.

Example 5

[0103] OH Group Substituted Quinazoline Compounds OH group substitutedquinazoline derivatives were synthesized and characterized as discussedabove for Example 1. The structures and physical data are shown below:No Name Structure Formula MW 1 P-93

C₁₆H₁₄ClN₃O₃ 331 2 P-97

C₁₆H₁₃Br₂N₃O₃ 455 3 P-131

C₁₆H₁₅N₃O₃ 297 4 P-132

C₁₆H₁₅N₃O₃ 297 5 P-133

C₁₉H₁₆N₄O₃ 348 6 P-150

C₁₅H₁₄N₄O₃ 298 7 P-154

C₁₆H₁₄BrN₃O₃ 376 8 P-180

C₁₆H₁₅N₃O₃ 297 9 P-182

C₁₇H₁₅N₃O₅ 341 10 P-189

C₁₆H₁₃Cl₂N₃O₃ 365 11 P-190

C₁₇H₁₆BrN₃O₃ 389 12 P-191

C₁₇H₁₇N₃O₃ 311 13 P-192

C₁₆H₁₅N₃O₄ 313 14 P-197

C₁₆H₁₄ClN₃O₃ 331 15 P-215

C₁₄H₁₃N₅O₄ 315 16 P-259

C₁₇H₁₇N₃O₃ 311 17 P-265

C₁₈H₁₉N₃O₃ 325 18 P-266

C₁₈H₁₉N₃O₃ 325 19 P-274

C_(2O)H₁₇N₃O₃ 347 20 P-275

C₂₀H₁₇N₃O₃ 347 21 P-276

C₁₈H₁₉N₃O₃ 325 22 P-277

C₂₈H₂₃N₃O₃ 449 23 P-278

C₁₆H₁₄ClN₃O₃ 331 24 P-289

C₁₈H₁₉N₃O₅ 357 25 P-292

C₂₀H₁₇N₃O₃ 341 26 P-293

C₂₀H₁₇N₃O₃ 341 27 P-294

C₁₆H₁₃I₂N₃O₃ 549 28 P-229

C₁₆H₁₄IN₃O₃ 423 29 P-312

C₁₆H₁₄N₄O₅ 342 30 P-313

C₁₆H₁₄N₄O₅ 342 31 P-315

C₁₆H₁₄N₄O₅ 342 32 P-323

C₁₆H₁₄N₄O₅ 3424-(3′-Chlooro-6′-hydroxylphenyl)amino-6,7-dimethoxyquinazoline (HI-P93)yield 93.08%; m.p. 295° C.(dec). ⁻H NMR-DMSO-d₆: δ 10.14(s, 1H, —NH),9.16(s, 1H, —OH), 8.37(s, 1H, 2-h), 7.78(s, 1H, 5H), 7.57(d, 1H,J_(2′,2′)=2.4 Hz, 2′-H), ), 7.16(s, 1H, 8-H), 7.07(dd, 1H, J_(2′,4′)=2.4Hz, J_(4′,5′)=8.7 Hz, 4′-H), 6.92(d, 1H, J_(4′,5′)=8.7 Hz, 5′-H),3.93(s, 3H, —OCH₃), 3.92(s, 3H, —OCH₃. UV(MeOH): 205, 229.0, 251.0,320.0 nm. IR(KBr)ν_(max): 3500(br), 3430, 2835, 1622, 1512, 1432, 1259cm⁻¹. GC/MS m/z 333(M⁻ = 2, 13.41), 332(M⁻ = 1, 9.73), 331(M⁺, 39.47),314(M⁺ —OH, 100.00), 298(7.64). Found: C, 52.25; H, 4.07; N, 11.39,C₁₆H₁₄ClN₃O₃.HCl requires: C, 52.32; H, 4.09; N, 11.44%.4-(3′,5′-Dibromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline-(HI-P97).Yield 72.80%; m.p. > 300.000. ¹H NMR(DMSO-d₆): δ 9.71(s, 1H, —NH),9.39(s, 1H, —OH), 8.48(s, 1H, 2-h), 8.07(s, 2H, 2′,6′-H), 7.76(s, 1H,5-H), 7.17(s, 1H, 8-H), 3.94(s, 3H, —OCH₃, 3.91(s, 3H, —OCH₃). UV(MeOH):208.0, 210.0, 245.0, 320.0 nm; IR(KBr)ν_(max): 3504(br), 3419, 2868,1627, 1512, 1425, 1250, 1155 cm⁻¹; GC/MS m/z 456(M¹ = 1, 54.40), 455(M⁻,100.00), 454(M⁻ 1, 78.01), 439(M⁻ —OH, 7.96), 376(M⁻ + 1 —Br, 9.76),375(M⁻ Br, 10.91), 360(5.23). Anal. (C₁₆H₁₃Br₂N₃O₃) C, H, N.4-(4′-Hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P131): yield84.29%; m.p. 245.0-248.0° C. IR(KBr)ν_(max): 3428, 2836, 1635, 1516,1443, 1234 cm: ¹H NMR(DMSO-d₆: δ 11.21(s, 1H, —NH), 9.70(s, 1H, —OH),8.74(s, 1H, 2-h), 8.22(s, 1H, 5-h), 7.40(d, 2H, J−8.9 Hz, 2′,6′-H),7.29(s, 1H, 8-H), 6.85(d, 2H, J=8.9 Hz, 3′,5′-H), 3.98(s, 3H, —OCH₃,3.97(s, 3H, —OCH₂). GC/MS m/z 298(M⁻ = 1, 100.00), 297(M⁻, 26.6), 296(M⁺− 1, 12.5). Anal. (C₁₆H₁₅N₃O₃HCl) Cl, H, N.4-(2′-Hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P132): yield82.49%; m.p. 255.0-258.0° C. IR(KBr)ν_(max): 3500(br), 3425, 2833, 1625,1512, 1456, 1251, 1068 cm⁻¹. ¹H NMR(DMSO-d₆): δ 9.78(s, 1H, —NH),9.29(s, 1H, —OH), 8.33(s, 1H, 2-h), 7.85(s, 1H, 5-H), 7.41-6.83(m, 4H,3′,4′,5′,6′-H), 7.16(s, 1H, 8-H), 3.93(s, 3H, —OCH₃, 3.92(s, 3H, —OCH₃),280(M⁺ —OH, 10.0). Anal. (C₁₆H₁₅N₃O₃, HCl) C, H, N.4-[(8′-Hydroxyquiline)-5′-Jamino-6,7-dimethoxyquinazoline (HI-P133)yield 83.51%; m.p. 238.0-239.0° C. ₁H NME(DMSO-d₆: δ 10.12(br, s, 1H,—NH), 8.93-7.09 M, 8H, 2,5,2,2′,3′,4′,6′,7′-H), 4.04(s, 3H, —OCH₃),3.96(s, 3H, —OCH₃). UV(MeOH): 204.0, 245.0, 332.0 nm. IR(KBr)ν_(max):3425(br), 2935, 1632, 1510, 1437, 1273 cm⁻¹. GC/MS m/z 349(M⁻ = 1,100.00), 348(m+, 26.56), 307(38.50), 289(21.00).4-[(3′-Hydroxylpyridine)-2′]-amino-6,7-dimethoxyquinazoline (HI-P150)Yield 78.65%; m.p. 185.0-187.0° C. ¹H NMR(DMSO-d₆): δ 10.08(br, s, 1H,—NH), 8.52(s, 1H, 2-H), 7.88-7.86(m, 1H, 6′-H), 7.60(s, 1H, 5-H),7.39-7.35(m, 1H, 4′-H), 7.32(s, 1H, 8-H), 6.63-6.58(m, 1H, 5′-H),5.96(s, 1H, —OH), 3.97(s, 3H, —OCH₃), 3.94(s, 3H, —OCH₃). UV(MeOH):204.0, 238.0, 321.0 nm. IR(KBr)ν_(max): 3500, 3446, 2960, 1475, 1236,1375, 1182 cm⁻¹. GC/MS m/z 299(M⁻ = 1, 100), 298(M⁺, 34), 289(11),291(9). Found: C, 60.26; H, 4.81; N, 18.68. C₁₅H₁₄N₄O₅, requires: C,60.26; H, 4.81; N, 18.68%.4-(3′-Bromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P154);yield 89.90%; m.p. 233.0-233.5° C. ¹H NMR(DMSO-d₆): 10.08(s, 1h, —NH),9.38(s, 1H, —OH), 8.40(s, 1H 2-H), 7.89(d, 1H, J_(2′,6′)=2.7 Hz, 2′-H),7.75(s, 1H, 5-h), 7.55(dd, 1H, J_(5′,6′)=9.0 Hz, J_(2′,6′)=2.7 Hz,6′-H), 7.14(s, 1H, 8-H), 6.97(d, 1H, J_(5′,6′)=9.0 Hz, 5′-H), 3.92(s,3H, —OCH₃), 3.90(s, 3H, —OCH₃). UV(MeOH): 203.0, 222.0, 25.0, 335.0 nm.IR(KBr)ν_(max): 3431(br), 2841, 1624, 1498, 1423, 1244 cm⁻¹. GC/MS m/z378(M⁺ = 2, 90.68), 377(M⁺ = 1, 37.49), 376(M⁺, 100.00), 360(MK⁺, 3.63),298(28.86), 282(6.65). Anal. (C₁₆H₁₄BrN₃O₃, HCl) C, H, N.4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (HI-P180) Yield71.55%; m.p. 256.0-258.0° C. IR(KBr)ν_(max): 3394, 2836, 1626, 1508,1429, 1251 cm⁻¹. ¹H NMR(DMSO-d₆): 9.41(s, 1H, —NH), 9.36(s, 1H, —OH),8.46(s, 1H, 2-H), 7.84(s, 1H, 5-H), 7.84-6.50(m, 4H, 2′,4′,5′,6′-H),7.20(s, 1H, 8-H), 3.96(s, 3H, —OCH³), 3.93(s, 3H —OCH₃). GC/MS m/z:(C₁₆H₁₅N₃O₃.HCl) C, H, N.4-(4′-Hydroxyl-3′-Carboxyphenyl)-amino-6,7-dimethoxyquinazoline(HI-P182) Yield 79.25%; m.p. > 300.0° C. ⁻H NMR(DMSO-d₆)I: δ 10.53(s,1H, —NH), 8.53(s, 1H, 2-H), 8.10-78.2(m, o3H, 2′, 5′, 6′, —H), 7.26(s,1H, 5-H), 6.9(s, 1H, 80H), 4.01(s, 3H, —OCH₃), 3.99(s, 3H, —OCH₃).UV(MeOH): 210.0, 239.0, 335.0 nm. IR(KBr)ν_(max): 3421, 2839, 1686,1631, 1508, 1491, 1280 cm⁻¹. GC/MS m/z 341(M⁺, 7.91), 323(M⁺ —OH,12.19), 297(M⁺ —COOH, 12.35), 296(M⁺ —COOH − 1.1760), 295(M⁺ —COOH − 2,28.65), 206(11.28).4-(4′-Hydroxyl-3′-5′-dicholophenyl-6,7-dimethoxyquinazoline (HI-P189)Yield 79.45%; m.p. 293.0-295.0° C. ¹H NMR(DMSO-d₆): 11.32(s, 1H, —NH),10.34(a, 1H, —OH), 8.87(s, 1H, 2-H), 8.29(s, 1H, 5-H), 7.90(s, 2H,2′,6′-H), 7.32(s, 1H, 8-H), 4.01(s, 3H, —OCH₃), 3.99(s, 3H, —OCH₃).UV(MeOH): 213.0, 232.0, 250.0, 335.0 nm. IR(KBr)ν_(max): 3479, 2564,1641, 1579, 1429, 1282, 1147 cm⁻¹. GC/MS m/z 367(M⁺ + 2; 66.57),366(M⁺ + 1, 75.91), 365(M⁺, 100.00), 364(M⁺ − 1, 94.08), 349(M⁻ OH,11.16. Anal. (C₁₆H₁₃Cl₂N₃O₃) C, H, N. Found: C, 48.93; H, 4.51; N,10.00. —H₁—Cl₂N₃O₃.HCl requires: C, 48.80; H, 4.31; N, 10.04%.4-(4′-Bromo-6′-Hydroxymethylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P190) Yield 7o3.08%; m.p. 222.0-223.0° C. ¹H NMR(DMSO-d₆): δ11.30(s, 1H, —OH), 8.22(s, 1H, —NH)O, 7.77.7.23(m, 5H, 5,8,2′,3′,5′-H),4.49(s, 2H, PhCH₂—H), 4.01(s, 3H, —OCH₃), 3.90(s, 3H, —OCH₃). UV(MeOH):207.0, 250.0, 332.0 nm. IR(KBr)ν_(max): 3446, 2829, 2752, 1652, 1560,1471, 1365, 1280 cm⁻¹. GC/MS m/z 391(M⁻ = 1, 29.33), 389(M⁻, 29.82),360(M⁻ CH²OH, 50.76), 358(52.39), 311(18.33), 280(43.20), 206(62.80),191(100.00). Anal. (C¹⁷H¹⁶BrN₃O_(3.)HCl) C, H, N.4-(6′-Hydroxymethylphenyl)-amino-6,7-dimethosyquinazoline (HI-P191)Yield 78.45%; m.p. 215.0-218.0° C. ¹H NMR(DMSO-d₆): δ 11.54(s, 1H,—NH)O, 8.70(s, 1H, 2-H), 8.34(s, 1H, 5-H), 7.62-7.33(m, 4H,3′,4′,5′,6′-H), 7.39(s, 1H, 8-H), 4.49(s, 2H, PhCH₂OH), 3.99(s, 3H,—OCH₃), 3.98(s, 3H, —OCH₃). UV9MeOH): 209.0, 224.0, 246.0, 335.0 nm.IR(KBr)ν_(max): 3421, 2941, 1675, 2606, ′128, 1508, 1437o, 1244 cm⁻¹.GC/MS m/z 311(M⁻, 38.07), 310(M⁻ − 1, 27.04), 28o0(M⁻ CH₂OH, 100.00),206(17.24), 191(51.34).4-(2′,4′-Dihydroxyphenyl)-amino-6,7-dimethoxyquinazoline (HI-P192) Yield86.25%; m.p. 240.0° C.(dec). ¹H NMR(DMSO-d₆): 10.92(s, 1H, —NH), 976(s,1H, —OH), 9.59(s, 1H, —OH), 8.67(s, 1H, 20H), 81.9(s, 1H, 8-H), 7.36(s,1H, 50H), 705(d, 1H, J−8.7 Hz, 1′-H), 6.51(s, 1H, 5′-H), 6.31(d, 1H,J−8.7 Hz, 3′-H), 3.98(s, 6H, —OCH₃). UV(MeOH): 206.0, 209.0, 223.0,250.0, 342.0, 486 nm. IR(KBR)ν_(max): 3391, 3139, 2938, 2850, 1633,1607, 1567, 1509, 1447, 1359, 1220, 1189, 1055 cm⁻¹. GC/MS m/z: 314(M⁻ =1, 13.00), 313(m⁻, 72.80), 312(m⁺ − 1, 10.20), 296(524), 206(17.50).4-(2′,3′-Dihydroxyphenyl)-amino-6,7-dimethoxyquinazoline (HI-P192) Yield86.25%; m.p 240.0° C.(dec). ¹H NMR(DMSO-d₆): 10.00(s, 1H, —NH), 9.37(s,1H, —OH), 8.41(s, 1H, 2-H), 7.78(s, 1H, 5-H), 7.49(d, 1H, J_(2′,3′)=2.7Hz, 2′-H), 7.55(dd, 1H, J_(5′,6′)=9.0 Hz, J_(2′,6′)=2.7 Hz, 6′-H),7.16(s, 1H, 8-H), 6.97(d, 1H, J_(5′,6′)=9.0 Hz, 5′-h), 3.93(s, 3H,—OCH₃), 3.91(s, 3H, —OCH₃). UV9MeOH): 209.0, 224.0, 249.0, 330.0 nm.IR(KBr)ν_(max): 3448, 2842, 1623, 1506, 1423, 1241 cm⁻¹. GC/MS m/z:341(M⁺, 100.00), 326(M⁻ CH₃, 98.50), 310(M⁺ —OCH₃, 12.5), 295(9.0),189(13.5), 155(13.8). Found: C, 52.35; H, 4.16; Cl, 19.15; N, 11.39.C₁₆H₁₄ClN₃O₃HCl requires: C, 52.32; H, 4.09; Cl, 19.07; N, 11.44%.4-(2′,4′-Dihydroxyl-1′,3′-diazine-5′)-amino-6,7-dime-thoxyquinazoline(HI-P215) (Yield 89.23%, m.p. > 300.0° C.) ¹H NMR(DMSO-d₆): δ 8.59(s,1H, 2-H), 7.89(s, 1H, 5-H), 7.60(d, 1H, 6′-H), 7.09(s, 1H, 8-H), 3.78(s,3H, —OCH₃), 3.76(s, 3H, —OCH₃). UV(MeOH): 222.0, 246.0, 331.0 nm.IR(KBr)ν_(max): 3446, 3212, 3057, 1750, 1682, 1620, 1590, 1511, 1420,1265 cm⁻¹. GC/MS m/z: 315(M⁻ .57.52), 206(46.50), 191(18.21),127(100.00). 4-(3′-Hydroxymethylphenyl)-amino-6,7-dimethoxyquina-zoline(HI-P259) Yield 74.28%; m.p. 230.0-232.0° C. ¹H NMR(DMSO-d₆): δ 11.29(s,1H, —NH), 8.83(s, 1H, 2-H)I, 8.28(s, 1H, 5-H), 7.61-7.25(m, 4H,2′,4′,5′,6′-H), 7.36(s, 1H, 8H)O, 4.57(s, 2H, —CH2OH), 4.02(s, 3H,—OCH₃), 4.00(s, 3H, —OC₃). UV(MeOH): 207.0, 224.0, 251.0, 334.0 nm.IR(KBr)ν_(max): 3500, 3029, 1639, 1589, 1514, 1456, 1284 cm⁻¹. GC/MSm/z: 281(M⁻ + 1 —CH₂OH, 54.00), 280(M⁻ —CH2OH, 100.00). Found: C, 58.68;H;, 5.30; N, 12.02. C₁₆H₁₅N₃O₂.HCl requires: C, 58.79; H, 5.19; N,12.10%. 4-[4′-(2″-Hydroxylethylphenyl)]-amino-6,7-dimethoxyqui-nazoline(HI-P265) Yield 92.30%; m.p. 235.0-240.0° C. ¹H NMR(DMSO-d₆): δ 11.44(s,1H, —NH), 8.79(s, 1H, 2-H), 8.34(s, 1H, 5-h)I, 7.56(d, 2H, J=8.1 Hz,2′,6′-H), 7.34(d, 2H, J−8.1 Hz, 3′,5′-H), 7.31(s, 1H, 8H), 4.00(s, 3H,—OCH₃), 3.99(s, 3H, —OCH₃), 3.64(t, 2H, j=6.9 Hz, 1″-H)I, 2.77(t, 2H,J=6.9 Hz, 2″-H). UV(MeOH): 204.0, 226.0, 251.0, 335.0 m. IR(KBr)ν_(max):3361, 3015, 27o6o7, 1628, 1581, 1514, 1432, 1282 cm⁻¹. GC/MS m/z:281(17.00), 253(10.00), 207(100.00).4-[2′-(2″-Hydroxylethylphenyl)]-amino-6,7-dimethoxyqui-nazoline (HIP266) Yield 87.69%; m.p/ 228.0-230.0° C. ¹H NMR-DMSO-d₆): δ 11.32(s, 1H,—NH), 8.74(s, 1H, 2′-H), 8.13(s, 1H, 5-H), 7.46-7.34(m, 4H,3′,4′,5,6′-H), 7.32(s, 1H, 8H), 4.00(s, 3H, —OCH₃), 3.99(s, eH, —OCH₃),3.58(t, 2H, J−7.2 Hz, 1″-H), 2.75(t, 2H, J=7.2 Hz, 2″-H). UV(MeOH):210.0, 226.0, 249.0, 332.0 nm. IR(KBr)ν_(max): 3366, 3226, 3056, 2917o,2685, 21638, 1571, 1514, 1467, 1277 cm⁻¹. GC/MS m/z: 281(20.00),253(9.00), 207(100.00).4-(1′-Naphthol-4′)-amino-6,7-edimethoxyquinazoline (HI-P274) Yield79.26; m.p. 205.0-208.0° C. ¹H NMR-DMSO-d₆): δ 11.64(s, 1H, —NH),10.61(s, 1H, —OH), 8.59(s, 1H, 2-h), 8.41(s, 1H, 5-H), 8.22-6.98(m, 5H,3′,5′,6′,7′,8′-H), 7.40(s, 1H, 8H), 4.00(s, 3H, —OCH₃), 3.99(s, 3H,—OCH₃). UV9MeOH): 208.0, 215.0, 225.0, 240.0, 330.0 nm. IR(KBr)ν_(max):3438, 3211, 3061, 2932, 2834, 1633, 1576, 1509, 1437, 1380, 1276, 1215cm⁻¹. GC/MS m/z: 281(51.00), 253(22.00), 207(88.00). Found: C, 62.26; H,4.87; N, 10.77. C₂₀H₁₇N₃O₃.HCl requires: C, 62.66; H, 4.70; N, 10.96%.4-(2′-Naphthol-1′)-amino-6,7-dimethoxyquinazoline (HI-P275) Yield83.17%; m.p. 218.0-220.0° C. ¹H NMR(DMSO-d₆): δ 11.33(s, 1H, —NH),10.22(s, 1H, —OH), 8.62(s, 1H, 2-H), 8.40(s, 1H, 5-H), 7.98-7.31(m, 6H,3′,4′,5′,6′,7″8′-H), 7.41(s, 1H, 8H), 4.02(s, 3H, —OCH₂), 4.00(s, 3H,—OCH₃), . UV(MeOH): 206.0, 210, 219.0, 225.0, 230.0, 340.0 nm.IR(KBr)ν_(max): 3391, 3165, 3051, 2938, 2840, 1628, 1576, 1504, 1437,1281, 1215 cm⁻¹. GC/MS m/z: 348(M⁻ ⁺1, 7.00), 347(M⁻, 100.00), 346(M⁻1.22.00), 331(15.00), 330(12.00), 281(23.00), 253(12.00), 207(49.00).Found: C, 62.91; H, 4.76; N, 10.75. C₂₀H₁N₃O₃.HCl requires: C, 62.66; H,4, 70; N, 10.96%.4-[3′-(1″-Hydroxyethyl)]-amino-6,7-dimethoxyquinazoline (HI-P276) Yield79.21%; m.p. 215.0-218.0° C. ¹H NMR(DMSO-d₆): δ 11.40(s, 1H, —NH),8.81(s, 1H, 20H), 8.31(s, 1H, 5-H)O, 7.60-7.26(m, 4H, 2′,4′,5′,6′-H),7.41(s, 1H, 8H), 4.65(q, 1H, J=6.6 Hz, —CH(OH)CH₃), 4.00(s, 3H, —OCH₃),3.98(s, 3H, —OCH₃), 1.350(d, 3H, J=6.6 Hz, —CH₃). UV9MeOH): 204.0,216.0, 220.0, 224.0, 250.00, 348.0 nm. IR(KBr)ν_(max): 3407, 3030, 2977,2840, 1643, 1591 1514, 1463, 1370, 1282, 1230 cm⁻¹. GC/MS m/z: 325(M⁻ +1, 67.00), 324(M⁻, 100.00), 323(M⁻ 1.22.00), 308(17.00), 307(56.00),306(21.00), 281(2.00), 280(8.00), 264(6.00).4-(4′-Hydroxy-3′,5′-diphenylphenyl)-amino-6,7-dime-hoxyquinazoline(HI-P277) Yield 76.11%; m.p. 255.0-257.0° C. ¹H NMR_DMSO-d₆): δ 11.50(s,1H, —NH), 8.80(d, d, 2H, 2′,6′-H), 8.58(s, 1H, 5-H), 7.60-7.30(m, 10H,3′, 5′, Ph—H), 7.39(s, 1H, 8H), 4.00(s, 3H, —OCH₃), 3.97(s, 3H, —OCH₃),1.350(d, eH, J=6.6 Hz, —CH₃). UV(MeOH): 210.0, 214.0, 229.0, 239.0,345.0, 248.0, 352.0 nm. IR(KBr)ν_(max): 3520, 3218, 3023, 2935, 1630,1562, 1518, 1457, 1281, 1234 cm⁻¹. GC/MS m/z: 281(35.00), 267(6.00),253(10.00), 207(100.00).4-(4′-Hydroxyl-2′-chlorophenyl)-amino-6,7-dimethoxy-quinazoline(HI-P2878) Yield 81.44%; m.p. 245.0-247.0° C. ¹H NMR(DMSO-d₆): δ11.39(s, 1H, —NH)O, 10.30(s, 1H, —OH), 8.75(s, 1H, 2-H), 8.24(s, 1H,5-H), 7.38-6.85(m, 3H, 3′,5′,6′-H), 7.37(s, 1H, 8H), 3.98(s, 3H, —OCH₃),3.96(s, H₃, —OCH₃). UV(MeOH): 222.0, 234.0, 239.0, 245.0, 254.0, 348.0nm. (R(KBr)ν_(max): 3448, 3242, 3144, 3025, 2917, 2834, 1638, 1591,1514, 1437, 1365, 1277, 1209 cm⁻¹. GC/MS c/z: 332(M⁻ + 1, 5.00), 331(M⁻,17.00), 330(M⁻ − 1, 5.00), 297(17.00), 296(100.00), 281(18.00),280o(29.00), 253(9.00).4-(2′-Hydroxy-naphthyl-3′)-amino-6,7-dimethoxyquinazolin (HI-P292) Yield87.41%; m.p. 277.0-279.0° C. ¹H NMR(DMSO-d₆): δ 11.38(s, 1H, —NH)O,10.35(s, 1H, —OH), 8.73(s, 1H, 2-H), 8.25(s, 1H, 5-H), 7.93-7.30(m, 6H,1′,4′,5′,6′,7′,8′-H), 7.37(s, 1H, 8H)O, 4.00(s, 6H, —OCH₃). UV(MeOH):204.0, 221.0, 224.0, 230.0, 256.0, 344.0 nm. IR(KBr)ν_(max): 3479, 3386,3036, 2901, 1632, 1581, 1504, 1437, 1281 cm⁻¹. GC/MS m/z: 281(41.00),253(11.00), 207(100.00). Found: C, 62.87; H;, 4.83; N, 1o0.78.C₂₀H₁N₃O₃.HCl requires: C, 62.66; H, 4.70, N, 10.96%.4-(1′-Hydroxy-naphthyl-5′)-amino-6,70-dimethoxyquina-zoline (HI-P293)Yield 87.21%; m.p. 204.0-205.0° C. ¹H NMR(DMSO-d₆): δ 11.73(s, 1H, —NH),10.43(s, 1H, —OH), 8.65(s, 1H, 2-H, 8.38(s, 1H, 5-H), 8.21-6.95(m, 6H,2′,3′,4′,6′,7′,8′-H), 7.33(s, 1H, 8H)O, 4.00(s, 6H, —OCH₃). UV9MeOH):204.0, 214.0, 224.0, 229.0, 235.0 348 nm. IR(KBrν_(max): 3449, 3335,3102, 2927o, 1633, 1571, 1509, 1437, 1287 cm⁻¹. Found: C, 62.23; H,4.96; N, 10.89. C₂₀H₁₇N₃O₃.HCl requires. C, 62.66; H, 4.70; N, 10.96%.4-(4′-Hydroxy-3,5-diiodophenyl)-amino-6,7-dimethoxy-quinazoline(HI-P294) Yield 77.47&; m.p. 259.0-260.0° C. ¹H NMR(DMSO-d₆): δ 11.13(s,1H, NH), 9.73(s, 1H, —OH), 8.87(s, 1H, 2-H), 8.16(s, 1H, 5-H), 8.09(s,2H, 1′,6′-H), 7.28(s, 1H, 8H), 3.98(s, 6H, —OCH₃),. UV(MeOH)λ_(max):217.0, 227.0, 252.00 nm. IR(KBrν_(max): 3457, 3201, 2934, 2832, 2566,1629, 1562, 1521, 1439, 1275, 1075 cm⁻¹. GC/MS m/z: GC/MS m/z 422(M⁻1.33.53), 405(7.50), 281(86.67), 221(51.80), 207(91.30). Found: C,32.60; H, 2.50; N, 6.92. C₁₆H₁₃I₂N₃O₃.HCl requires: C. 32/82.′ J. 2.39;N, 7.18%. 4-(4′-Hydroxy-3′-iodophenyl)-amino-6,7-dimethoxyquinazoline(HI-P299) Yield 71.59%; m.p. 248.0-250.0° C. ¹H NMR(DMSO-d₆): δ 11.32(d,1H, NHO), 10.62(s, 1H, —OH, 8.79(s, 1H, 2-H), 8.26(s, 1H, 5-H),7.98-6.98(m, 3H, 2′,3′,6′-H), 7.32(s, 1H, 8H), 3.98(s, 3H, —OCH₃),3.97(s, 3H, —OCH₃). UV(MeOH)λ_(max)(ε): 217.0, 227.0, 252.0 nm.IR(KBr)ν_(max): 3411, 2975, 2730, 2366, 1634, 1573, 1501, 1429, 1229,1075 cm⁻¹. GC/MS m/z: 406(M⁻ 1.3.33), 405(M⁻ 2, 7.50), 281(M⁺ − 1 —I,26.67), 253(11.80), 207(100.00). Found: C, 41.96; H, 3.40; N, 8.98.C₁₆H₁₄IN₃O₃.HCl requires: C, 41.83; H, 3.26; N, 9.15%.

[0104] TABLE 5 Fluoroquinazoline Derivatives

(HI-P352) (HI-P353) No R Formular MW HI-P144 2-F, 3-F, 5-F, 6-F, 4-BrC₁₆H₁₀BrF₄N₃O₂ 432 HI-P214 2-F, 4-Br C₁₆H₁₃BrFN₃O₂ 378 HI-P218 3-CF₃C₁₇H₁₄F₃N₃O₂ 349 HI-P219 4-OCF₃ C₁₇H₁₄F₃N₃O₃ 365 HI-P221 4-F C₁₆H₁₄FN₃O₂299 HI-P223 4-CF₃ C₁₇H₁₄F₃N₃O₂ 349 HI-P224 3-F C₁₆H₁₄FN₃O₂ 299 HI-P2282-CF₃ C₁₇H₁₄F₃N₃O₂ 349 HI-P232 4-SO₂F C₁₆H₁₄FN₃O₄S 363 HI-P264 2-FC₁₆H₁₄FN₃O₂ 299 HI-P352 * C₂₅H₂₀F₆N₄O₂ 522 HI-P353 * C₂₅H₂₀F₆N₄O₂ 522HI-P364 3-OCF₃ C₁₇H₁₄F₃N₃O₃ 365 HI-P365 2-OCF₃ C₁₇H₁₄F₃N₃O₃ 365 HI-P3663-CF₃, 5-CF₃, C₁₈H₁₃F₆N₃O₂ 417 HI-P367 2-CF₃, 5-CF₃, C₁₈H₁₃F₆N₃O₂ 417HI-P369 3-F, 4-OH C₁₆H₁₄FN₃O₃ 315 HI-P408 3-F, 5-F, 4-OH C₁₆H₁₃F₂N₃O₃333

HI-P352

HI-P353

Example 6

[0105] Fluorine Substituted Quinazoline Compounds Fluorine substitutedquinazoline derivatives were synthesized and characterized as discussedabove for Example 1. The structures and physical data are shown below:No Name Structure Formula MW 1 P-144

C₁₆H₁₀BrF₄N₃O₂ 432 2 P-214

C₁₆H₁₃BrFN₃O₂ 378 3 P-218

C₁₇H₁₃F₄N₃O₂ 367 4 P-219

C₁₇H₁₄F₃N₃O₃ 365 5 P-221

C₁₆H₁₄FN₃O₂ 299 6 P-223

C₁₇H₁₄F₃N₃O₂ 349 7 P-224

C₁₆H₁₄FN₃O₂ 299 8 P-228

C₁₇H₁₄F₃N₃O₂ 349 9 P-232

C₁₆H₁₄F₂SN₃O₄ 363 10 P-264

C₁₆H₁₄FN₃O₂ 299 11 P-352

C₂₅H₂₀F₆N₄O₂ 522 12 P-353

C₂₅H₂₀F₆N₄O₂ 522 13 P-364

C₁₇H₁₄F₃N₃O₃ 365 14 P-365

C₁₇H₁₄F₃N₃O₃ 365 15 P-366

C₁₈H₁₃F₆N₃O₂ 417 16 P-367

C₁₈H₁₃F₆N₃O₂ 417 17 P-369

C₁₆H₁₄FN₃O₃ 315 18 P-408

C₁₆H₁₃F₂N₃O₃ 3334-(2′,3′,5′,6′-Terrafluoro-4′-bromophenyl)-amino-6,7-dime-thoxyquinazoline(HI-P144) The yield 78.24%: m.p. 180.0-182.0° C. ¹H NMR(DMSO-d₆): δ7.78(s, 1H, 2-H), 7.53(s, 1H, 5-H), 6.79(s, 1H, 8-H), 3.81(s, 3H,—OCH₃), 3.3.79(s, 3H, —OCH₃). Found: C, 41.12; H, 2.41; N, 9.89,C₁₀H₁₀BrF_N₃O₂.HCl. requires: C, 41.11; H, 2.36; N, 9.93%.4-(2′-Fluoro-4′-bromophenyl)-amino-6,7-dimethoxyquina-zoline (HI-P214)The yield 77.21%; m.p. 247.0-252.0 0° C. ¹H NMR(DMSO-d₆): δ 8.57(s, 1H,2-H), 7.91(s, 1H, 5-H), 7.57(d, 1H, 3′-H), 7.34(m, 2H, 5′,6′-H), 7.07(s,1H, 8-H), 3.78(s, 3H, —OCH₃), 3.77(s, 3H, —OCH₃). UV(MeOH): 204.0,215.0, 250.0, 330.0 nm. IR(KBr)ν_(max): 3431, 2629, 1633, 1580, 1511,1420, 1278 cm⁻¹. GC/MS m/z 379(M⁺ + 1, 34.39), 378(M⁻, 31.33), 377(M⁻ −1, 39.08), 360(62.05), 359(31.58), 358(62.57), 357(19.81), 299(19.31),298(100.00), 282(17.88), 240(28.76).4-(3′-Trifluoromethylphenyl)-amino-6,7-dimethoxyquinazo-line (HI-P218)The yield 85.61%: m.p. 242.0-245.0 0° C. ¹H NMR(DMSO-d₆): δ 11.09(s, 1H,—NH), 8.67(s, 1H, 2-H), 8.03(s, 1H, 5-H), 7.92-7.43(m, 4H, 2′4′5′,6′-H),7.10(s, 1H, 8-H), 3.81(s, 3H, —OCH₃), 3.79(s, 3H, —OCH₃). UV(MeOH):206.0, 276.0, 349.0 nm. IRν_(max)(KBr): 3372, 3257, 2935, 1626, 1512,1380, 1225 cm⁻¹. GC/MS m/z 350(M⁺ + 1, 10.5), 249(M⁻, 85.5), 173(M⁻ − 1,100.0), 332(10.5), 290(8.8).4-(4′-Trifluoromethoxylphenyl)-amino-6,7-dimethoxyqui-nazoline (HI-P219)The yield 83.14%; m.p. 228.0-230.0 0° C. ¹H NMR(DMSO-d₆): δ 11.39(s, 1H,—HN), 8.63(s, 1H, 2-H), 8.18(s, 1H, 5-H), 7.63(t, 2H, 3′,5′-H), 7.27(t,2H, 2′,6′-H), 7.15(s, 1H, 8-H), 3.81(s, 3H, —OCH₃), 3.78(s, 3H, —OCH₃).UV(MeOH): 209.0, 216.0, 251.0, 332.0 nm. IR(KBr)ν_(max): 3207, 2839,2762, 1633, 1508, 1480, 1276 cm⁻¹. GC/MS m/z 366(M⁺ + 1, 12.50), 365(M⁻,75.00), 364(M⁻ − 1, 100.00), 348(17.50), 319(19), 306(8.00), 207(15.00).4-(4′-Fluorophenyl)-amino-6,7-dimethoxyquinazoline (HI-P221) The yield84.25%: ¹H NMR(DMSO-d₆): δ 11.19(s, 1H, —HN), 8.60(s, 1H, 2-H), 8.08(s,1H, 5-H), 7.50(t, 2H, 3′-H), 7.13(s, 1H, 8-H), 7.12(t, 2H, 2′,6′-H),3.79(s, 3H, —OCH₃), 3.78(s, 3H, —OCH₃). UV(MeOH): 225.0, 251.0, 333.0nm. IR(KBr)ν_(max): 3205, 3007, 2837, 1633, 1580, 1508, 1470, 1220 cm⁻¹.GC/MS m/z 300(M⁺ + 1, 10.76), 299(m⁻, 76.92), 39.8(M⁻ − 1, 100.00),282(20.00), 253(13.08), 207(3.80). Found: C, 57.17; H, 4.37; N, 12.47,C₁₆H₁₄FN₃O₂.HCl requires C, 57, 31; H, 4.48; N, 12.54%.4-(4′-Trifluoromethylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P223)The yield 91.70%: m.p. 243.0-245.0 0° C. ¹H NMR(DMSO-d₆): δ 11.47(s, 1H,—NH), 8.67(s, 1H, 2-H), 8.23(s, 1H, 5-H), 7.79(d, 2H, J=8.4 Hz, 3′5′-H),7.61(d, 2H, J=8.4 Hz, 2′6′-H), 7.17(s, 1H, 8-H), 3.82(s, 3H, —OCH₃),3.78(s, 3H, —OCH₃). GC/MS m/z 350(M⁻ + 1, 11.00), 349(M⁻, 65.00), 348(M⁻− 1, 100.00), 332(18.50), 303(10.00), 207(18.50). Found: C, 53.01; H,3.94; N, 10.88. C₁—H₁₄F₃N₃O₂HCl requires C, 52.98; H, 3.90; N, 10.91%.4-(4′-Flurophenyl)-amino-6,7-dimethoxyquinazoline (HI-P224) The yield88.69%; m.p. 254.0-255.0 0° C. ¹H NMr(DMSO-d₆): δ 11.16(s, 1H, —HN),8.67(s, 1H, 2-H), 8.09(s, 1H, 5-H), 7.13(s, 1H, 8-H), 7.51-6/94(m, 4H,2′,3′,5′,6′-H)O, 3.80(s, 3H, —OCH₃), 3.79(s, 3H, —OCH₃). UV(MeOH):206.0, 226.0, 251.0, 333.0, 343 nm. IR(KBr)ν_(max): 3437, 3211, 2619,1637, 1580, 1500, 1448, 1281 cm⁻¹. GC/MS m/z (300(M⁺ + 1, 8.00), 299(M⁻,68.00), 398(M⁻ 1, 100.00), 282(21.60), 253(25.00), 207(80.00),. Found:C, 57.25; H, 4.58; N, 12.42. C₁₆H₁₄FN₃O₂.Hcl requires C, 57.31; H, 4.48;N, 12.54%. 4-(2′-Trifluoromethylphenyl)-amino-6,7-dimethoxyquinazoline(HI-P228). The yield 83.57%; m.p. 242.0-245.0 0° C. ¹H NMR(DMSO-d₆): δ11.58(s, 1H, —HN), o8.76(s, 1H, 2-H), 8.25(s, 1H, 5-H), 7.95-7.62(m, 4H,3′,4′,5′,6′-H), 7.38(s, 1H, 8H), 4.01(S, 3H, —OCH₃), 3.00(s, 3H, —OCH₃).GC/MS m/z 350(M⁻ + 1, 8.50), 349(M⁻, 32.00), 348(M⁺ − 1.31.50),328(18.50), 207(5.0)I, 280(M⁺ —CF₃, 100.00), 264(18.50), 207(32.50).Found: C, 52.71; H, 4.26; N, 10.91%. 4-[4′-benzenesulfanilylfluoride]-amino-6,7-dimethoxyquinazoline (HI-P232) Yield 84.02%; m.p.228.0-230.0° C. ¹H NMR9DMSO-d₆): δ 11.62(s, 1H, —HN), 8.78(s, 1H, 2-H),8.29(s, 1H, 5-H), 8.12-8.02(m, 4H, 2″,3″,5″,6″-H), 7.21(s, 1H, 8-H),3.86(s, 3H, —OCH₃), 3.81(s, 3H, —OCH₃). UV(MeOH): 208.0, 215.0, 253.0,278.0, 338.0 nm. IR(KBr)ν_(max): 3440, 3277, 2571, 1635, 1580, 1516,1435, 1209 cm⁻¹. GC/MS m/z: 281(43.00), 253(12.00), 207(100.00). Found:C, 48.13; H, 3.73; N, 10.53. C₁₆H₁₄FN₃O₄S.HCl requires: C, 48.12; H,3.76; N, 10.53%. 4-(2′-Fluorophenyl)-amino-6,7-dimethoxyquinazoline(HI-P264) Yield 73.58%; m.p. 233.0-235.0 0° C. ¹H NMR(DMSO-d₆): δ11.69(d, 1H, —NH), 8.82(s, 1H, 2-H), 8.37(s, 1H, k 50H), 7.59-7.32(m, 4H3′,4′5′,6′-H), 7.41(s, 1H, 8H)O, 4.02(s, 3H, —OCH₃), 4.01(s, 3H, —OCH₃).UV(MeOH): 204.0, 226.0, 248.0, 330.0 nm. IR(KBrν_(max): 3454, 3032,2638, 1630, 1589, 1514, 1430, 1291 cm⁻¹. GC/MS m/z 300(M⁺ = 1, 7.00),299(M⁻, 38.00), 298(M⁻ 1.22.00), 280(M⁻ F, 100.00), 264(15.00),207(35.00). Found: C, 57.12; H, 4.57; N, 12.45. C₁₆H₁₄FN₃O₂.HClrequires: C, 57.31; H, 4.48; N, 12.54%.4-{4′-[2″-(4′′′-Aminophenyl)-hexafluoropropyl]phenyl}-amino-6,7-dimethoxyquinazoline(HI-P352) Yield, 80.41%, m.p. 280.0-282.0° C. ¹H NMR(DMSO-d₆): δ11.87(s, 1H, —NH), 8.91(s, 1H, 2-H)I, 8.55-7.18(m, 10H,5,8,2′,3′,5′,6′,2′′′,3′′′,5′′′,6′′′-H), 4.05(s, 3H, —OCH₃), 4.00(s, 3H,—OCH₃). ¹⁹F NMR(DMSO-d₆): 128.76. Found: C, 50.33; H, 3.87; N, 9.57.C₂₅H₂₀F₆N₄O₂.2HCl requires: C, 50.50; H, 3.70; N, 9.42%4-{3′-[2″-(3′′′-Aminophenyl)-hexafluoropropyl]phenyl}-amino-6,7-dimethoxyquinazoline (HI-P353) Yield, 83.11%, m.p. 292.0-284.0° C. ¹HNMR(DMSO-d₆): δ 11.68(s, 1H, —NH), 8.81(s, 1H, 2-H), 8.44-7.09(m, 10H,5,8,2′,4′,5′,6′,2′′′,4′′′,5′′′6′′′-H). 4.00(s, 3H, —OCH₃), 3.97(s, 3H,—OCH₃). ¹⁹F NMR(DMSO-d₆): 129.21. Found: C, 53.96; H, 3.93; N, 9.77.C₂₅H₂₀F₆N₄O₂.HCl requires: C, 53.76; H, 3.76; N, 10.03%4-(3′-Trifluoromethoxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P364)Yield, 83.25%. m.p. 233.0-235.0° C. ¹H NMR(DMSO-d₆): δ 11.65(s, 1H,—NH), 8.88(s, 1H, 2-H), 8.41(s, 1H, 5-H), 7.86-7.29(m, 4H,2′,4′,5′,6′-H), 7.36(s, 1H, 8-H), 4.02(s, 3H, —OCH₃). 3.98(s, 3H,—OCH₃). ¹⁹F NMR(DMSO-d₆): 135.37. GC/MS m/z: 366(M⁺ + 1, 11.0), 365(M⁺,67.0), 364(M⁺ − 1, 100.0). Found: C, 50.93; H, 3.75; N, 10.61.C₁₇H₁₄F₃N₃O₃.HCl requires: C, 50.97; H, 3.74; N, 10.47%.4-(2′-Trifluoromethoxylphenyl)-amino-6,7-dimethoxyquinazoline (HI-P365)Yield, 77.85%. m.p. 235.0-237.0° C. ¹H NMR(DMSO-d₆): δ 11.68(s, 1H,—NH), 8.80(s, 1H, 2-H), 8.32(s, 1H, 5-H), 7.64-7.53(m, 4H,3′,4′,5′,6′-H), 7.40(s, 1H, 8-H), 3.99(s, 6H, —OCH₃). ¹⁹F NMR(DMSO-d₆):135.71. GC/MS m/z: 366(M⁻ + 1, 2.0), 365(M⁺, 15.0), 364(M⁺ − 1, 4.0),281(21.0), 280(M⁻ —OCF₃ 100). Found: C, 50.83; H, 3.79; N, 10.52.C_(1—)H₁₄F₃N₃O₃.HCl requires: C, 50.87; H, 3.74; N, 10.47%.4-(3′,5′-Ditrifluoromethylphenyl)-amno-6,7-dimethoxyquinazoline(HI-P366) Yield, 82.88% m.p. 270.0-272.0° C. ¹H NMR(DMSO-d₆): δ 11.87(s,1H, —NH), 8.97(s, 1H, 2-H), 8.60)s, 2H, 2′,6′-H), 8.43(s, 1H, 5-H),7.98(s, 1H, 4′-H), 7.35(s, 1H, 8-H), 4.03(s, 3H, —OCH₃). 3.99(s, 3H,—OCH₃). ¹⁹F NMR(DMSO-d₆): XX GC/MS m/z: 418(M⁻ + 1, 19.0), 417(M⁻,100.0), 416(M⁻ − 1, 73.0), 398(M⁻ —F, 16.0), 398(M⁻ —F, 16.0), 348(M⁻—CF₃, 16.0). Found: C, 47.78; H, 3.20; N, 9.26. C₁₈H₁₃F₆N₃O₂.HClrequires: C, 47.68; H, 3.09; N, 9.27%.4-(4′-Hydroxyl-3′-fluorophenyl)-amino-6,7-dimethoxyquinazoline (HI-P369)Yield, 84.28%. m.p. 268.0-270.0° C. ¹H NMR(DMSO-d₆: δ 11.36(s, 1H, —NH),10.13(s, 1H, —OH), 8.80(s, 1H, 2-H), 8.30(s, 1H, 5-H), 7.60-7.02(m, 3H,2′,5′,6′-H), 7.31(s, 1H, 8-H), 3.99(s, 3H, —OCH₃), 3.97(s, 3H, —OCH₃).¹⁹F NMR(DMSO-d₆): δ 57.38. Found: C, 54.90; H, 4.28; N, 11.91.C₁₆H₁₄FN₃O₃.HCl requires C, 54.70; H, 4.27; N, 11.97%.4-(4′-Hydroxyl-3′,5′-difluorophenyl)-amino-6,7-dimethoxy-quinazoline(HI-P408) Yield, 83.15%, m.p. 228.0-230.0° C. ¹H NMR(DMSO-d₆): δ11.46(s, 1H, —NH), 10.39(s, 1H, 2-H), 8.36(s, 1H, 5-H), 7.56, 7.54 (s,s, 2H, 2′,6′-H), 7.33(s, 1H, 8-H), 4.00)s, 3H, —OCH₃), 3.98(s, 3H,—OCH₃). ¹⁹F NMR(DMSO-d₆: δ 60.25, 60.22. Found: C, 52.04; H, 4.17; N,11.10. C₁₆H₁₃F₂N₃O₃.HCl. requires C, 52.03; H, 3.79; N, 11.38%.

Example 7 Anti-Tumor Activities of Specific Quinazoline Compounds

[0106] The cytotoxicity of the substituted quinazoline derivativecompounds against a variety of human tumor cells was evaluated. Therelative importance of particular substituent groups on the compoundswas also studied. The substituted quinazoline derivative compounds,prepared as described above, were tested, along with DMSO as a control.

[0107] Cytotoxicity Assay

[0108] The cytotoxicity assay of various compounds against human tumorcell lines was performed using the MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay(Boehringer Mannheim Corp., Indianapolis, Ind.). Briefly, exponentiallygrowing tumor cells were seeded into a 96-well plate at a density of2.5×10⁴ cells/well and incubated for 36 hours at 37° C. prior to drugexposure. On the day of treatment, culture medium was carefullyaspirated from the wells and replaced with fresh medium containing thequinazoline compounds at concentrations ranging from 0.1 to 250 μM.Triplicate wells were used for each treatment.

[0109] Human cell lines were obtained from American Type CultureCollection (Rockville, Md.) and maintained as a continuous cell line inDulbecco's modified Eagles' medium supplemented with 10% fetal bovineserum and antibiotics. Cells used in this study include human leukemiacells (NALM-6 and MOLT-3), human breast cancer cells (BR20), humanprostate cancer cells (PC3), and human brain tumor cells (U373).

[0110] The cells were incubated with the various compounds for 24-36hours at 37° C. in a humidified 5% CO₂ atmosphere. To each well, 10 μlof MIT (0.5 mg/ml final concentration) was added and the plates wereincubated at 37° C. for 4 hours to allow MTT to form formazan crystalsby reacting with metabolically active cells. The formazan crystals weresolubilized overnight at 37° C. in a solution containing 10% SDS in 0.01M HCl. The absorbance of each well was measured in a microplate reader(Labsystems) at 540 nm and a reference wavelength of 690 nm. Totranslate the OD 540 values into the number of live cells in each well,the OD 540 values were compared to those on standard OD 540-versus-cellnumber curves generated for each cell line. The percent survival wascalculated using the formula:${\% \quad {Survival}} = {\frac{{{live}\quad {cell}\quad {{number}\lbrack{test}\rbrack}}\quad}{{live}\quad {cell}\quad {{number}\lbrack{control}\rbrack}} \times 100}$

[0111] The IC₅₀ values were calculated by non-linear regressionanalysis.

[0112] Detection of Apoptosis

[0113] The demonstration of apoptosis was performed by the in situnick-end-labeling method using ApopTag in situ detection kit (Oncor,Gaithersburg, Md.) according to the manufacturer's recommendations.Exponentially growing cells were seeded in 6-well tissue culture platesat a density of 50×10⁴ cells/well and cultured for 36 hours at 37° C. ina humidified 5% CO₂ atmosphere. The supernatant culture medium wascarefully aspirated and replaced with fresh medium containingunconjugated EGF or EGF-P154 at a concentration of 10, 25, or 50 μg/ml.After a 36 hour incubation at 37° C. in a humidified 5% CO₂ incubator,the supernatants were carefully aspirated and the cells were treated for1-2 minutes with 0.1% trypsi The detached cells were collected into a 15mil centrifuge tube, washed with medium and pelleted by centrifugationat 1000 rpm for 5 minutes. Cells were resuspended in 50 μl of PBS,transferred to poly-L-lysine coated coverslips and allowed to attach for15 minutes. The cells were washed once with PBS and incubated withequilibration buffer for 10 minutes at room temperature.

[0114] After removal of the equilibration buffer, cells were incubatedfor 1 hour at 37° C. with the reaction mixture containing terminaldeoxynucleotidyl transferase (TdT) and digoxigenin-11-UTP for labelingof exposed 3′-hydroxyl ends of fragmented nuclear DNA. The cells werewashed with PBS and incubated with anti-digoxigenin antibody conjugatedto FITC for 1 hour at room temperature to detect the incorporated dUTP.After washing the cells with PBS, the coverslips were mounted ontoslides with Vectashield containing propidium iodide (Vector Labs,Burlingame, Calif.) and viewed with a confocal laser scanningmicroscope. Non-apoptotic cells do not incorporate significant amountsof dUITP due to lack of exposed 3-hydroxyl ends, and consequently havemuch less fluorescence than apoptotic cells which have an abundance ofexposed 3′-hydroxyl ends. In control reactions, the TdT enzyme wasomitted from the reaction mixture.

[0115] Results:

[0116] The cytotoxicity results for each tested group of compounds isshown in Tables 1-5 below: TABLE 1 Cytotoxic Activity of BromoSubstituted Quinazoline Compounds against Leukemic (NALM-6 & MOLT-3) andBreast Cancer (BT-20) NALM-6 MOLT-3 BT20 IC50 IC50 IC50 Drug (μM) (μM)(μM) HI-P79  142.1 194.9 201.5 HI-P88  >250 >250 >250 HI-P97  >250 >25026.1 HI-P111 200.6 >250 >250 HI-P154 12.5 9.1 >250 HI-P160 135.2 240.725.5 HI-P164 >250 >250 39.2 HI-P190 >250 >250 >250HI-P210 >250 >250 >250 HI-P211 >250 >250 >250 HI-P212 52.7 54.5 >250HI-P214 >250 >250 >250 Hl-P222 34.0 48.3 >250 HI-P234 >250 >250 >250HI-P241 >250 >250 >250 HI-P258 >250 >250 >250 HI-P260 32.4 51.3 82.1HI-P261 72.6 148.5 218.6 HI-P262 >250 >250 >250

[0117] TABLE 2 Cytotoxic Activity of Chloro Substituted QuinazolineCompounds against Leukemic (NALM-6 & MOLT-3) and Breast Cancer (BT-20)NALM-6 MOLT-3 BT20 IC50 IC50 IC50 Drug (μM) (μM) (μM) HI-P87 95.9 >104.6 >250 HI-P93  >250 >250 >250 HI-P189 >250 >250 >250 HI-P19739.3 68.0 136.9 HI-P239 29.6 28.7 25.7 HI-P246 >250 >250 >250 HI-P268215.2 227.4 121.5 HI-P269 >250 >250 >250 HI-P415 67.9 >250 38.1

[0118] TABLE 3 Cytotoxic Activity of Iodide Substituted QuinazolineCompounds against Leukemic (NALM-6 & MOLT-3), Breast Cancer (BT-20) andBrain Tumor (U373) cells NALM-6 MOLT-3 BT20 U373 IC50 IC50 IC50 IC50Drug (μM) (μM) (μM) (μM) HI-P270 >250 78.9 >250 >250 HI-P271 6.19.6 >250 >250 HI-P294 >250 >250 >250 >250 HI-P299 15.4 60.1 >250 >250HI-P300 58.0 59.1 72.6 116.2

[0119] TABLE 4 Cytotoxic Activity of OH Substituted QuinazoklineCompounds against Leukemic (NALM-6 & MOLT-3), Breast Cancer (BT-20) andBrain Tumor (U373) cells NALM-6 MOLT-3 BT20 U373 IC50 IC50 IC50 IC50Drug (μM) (μM) (μM) (μM) HI-P93  >250 >250 >250 >250 HI-P97  >250 >25026.1 161.2 HI-P131 32.1 38.6 >250 >250 HI-P154 12.5 9.1 >250 167.4HI-P189 >250 >250 >250 >250 HI-P190 >250 >250 >250 >250HI-P192 >250 >250 >250 >250 HI-P197 68.5 63.8 71.5 >250HI-P294 >250 >250 >250 >250 HI-P299 66.3 51.2 >250 >250

[0120] TABLE 5 Cytotoxic activity of fluoro-substituted dimethoxyquinazolines on cancer cells. NALM-6 MOLT-3 U373 BT20 PC3 IC50 IC50 IC50IC50 IC50 Compound (μM) (μM) (μM) (μM) (μM) HI-P144 28.1 ± 2.6 24.9 ±3.7  49.5 ± 11.3 63.4 ± 5.5 >250 Hl-P214 >250 >250 >250 >250 >250HI-P218 37.0 ± 5.8 33.2 ± 3.3 29.9 ± 7.3 37.62 ± 5.2  126.1 ± 5.8 HI-P219 22.3 ± 3.0 41.3 ± 4.4 83.6 ± 6.5  44.2 ± 10.9 58.3 ± 3.2 HI-P221100.5 ± 4.8  98.73 ± 3.8   28.8 ± 12.7 30.67 ± 7.9  >250 HI-P223 39.5 ±8.0  40.8 ± 15.1 32.1 ± 3.9 27.56 ± 8.6  >250 HI-P224 20.15 ± 8.1  23.3± 7.7 22.4 ± 5.9 58.33 ± 5.8  >250 HI-P228  57.3 ± 24.8 237.1 ±4.8  >250 >250 >250 HI-P232 41.4 ± 6.9 43.6 ± 2.3 207.7 ± 18.1 70.54 ±8.2   88.9 ± 17.2 HI-P264  47.0 ± 19.5  70.9 ± 17.3 53.3 ± 6.7 33.33 ±7.5  >250 HI-P352  7.1 ± 1.8 21.8 ± 1.7  65.5 ± 11.2  50.3 ± 14.8 72.6 ±2.5 HI-P353  6.1 ± 1.4 17.4 ± 1.5 14.5 ± 7.6 14.1 ± 3.3  64.9 ± 11.9HI-P364  7.9 ± 1.9 25.3 ± 9.1 27.7 ± 1.2 40.1 ± 8.6 >250 HI-P365 86.5 ±3.4 110.7 ± 7.5  >250 >250 >250 HI-P366  52.8 ± 14.0 137.2 ± 10.3  55.5± 13.2 61.7 ± 12.1 >250 HI-P369 >250 >250 >250 >250 >250 HI-P408 116.3 ±17.8 228.5 ± 20.8 >250 >250 >250

[0121] The compounds were tested for activity against various cancercells. For example, NALM-6 cells were incubated with HI-P144, HI-P214,HI-P221, HI-P224,.HI-P258, HI—P264, HI-P218, HI-P223, HI-P228, HI-P366,HI-P367, HI-P219, HI-P352, HI-P353, HI-P364 or HI-P365 for 24 hours in96-well plates and cell survival was determined by MTT assay. The datapoints represent the means (±SE) values from 3 independent experiments.

[0122] BT-20 breast cancer cells were incubated with HI-P144, HI-214,HI-P221, HI-P224, HI-P258, HI-P264, HI-P218, HI-P223, HI-P228, HI-P366,HI-P367, HI-P219, HI-P352, HI-P353, HI-P364, or HI-P365 for 24 hours in96-well plates and cell survival was determined by MTT assay. The datapoints represent the mean (±SE) values from 3 independent experiments.

[0123] Apoptosis was induced by the compounds. The cells were incubatedwith HI-P353 or HI-P219 for 24 hours, fixed, permeabilized, andvisualized for DNA degradation in a TUNEL assay usingdigoxigenin-UTP-labeling kit. In the color photographs, red fluorescencerepresents nuclei stained with propidium iodide. Green or yellow (i.e.,superimposed red plus green) represents the apoptotic nuclei. Shown arecontrol NALM-6 (FIG. 3A) and BT-20 (FIG. 3B) cells; HI-P353 treated NALM(FIG. 3D) and BT-20 cells (FIG. 3E); and control (FIG. 3C) and HI-P219treated PC3 cells (FIG. 3F).

Example 8 Pharmacokinetic Studies

[0124] In pharmacokinetic studies, mice were injected eitherintravenously (i.v.) via the tail vein or intraperitoneally (i.p.) witha bolus dose of 300 μg/mouse (˜12.5 mg/kg=34 μmols/kg) of HI-P131. Bloodsamples were obtained from the ocular venous plexus by retroorbitalvenupuncture prior to and at 3 minutes, 5 minutes, 10 minutes, 15minutes, 30 minutes, 45 minutes and 1 hour, 2 hours, 4 hours, and 8hours after administration of HI-P131. All collected blood samples wereheparinized and centrifuged at 7,000×g for 10 minutes in amicrocentrifuge to obtain plasma. The plasma samples were stored at −20°C. until analysis. Aliquots of plasma were used for extraction and HPLCanalysis. Pharmacokinetic modeling and pharmacokinetic parametercalculations were carried out using the pharmacokinetics software,WinNonline Program, Version 1.1. (Scientific Consulting Inc., Cary,N.C.). Concentration data were weighted by I/concentration. Anappropriate pharmacokinetic model was chosen on the basis of lowestweighted squared residuals, lowest Schwartz criterion (SC), lowestAkaike's Information Criterion (AIC) value, lowest standard errors ofthe fitted parameters, and dispersion of the residuals. The eliminationhalf-life was estimated by linear regression analysis of the terminalphase of the plasma concentration profile. The area under theconcentration time curve (AUC) was calculated by the trapezoidal rulebetween first (0 h) and last sampling time plus C/k, where C is theconcentration of last sampling and k is the elimination rate constant.Systemic clearance (CL) was determined by dividing the dose by the AUC.The apparent volume of distribution at steady-state was calculated usingthe following equation, V_(ss)=Dose·AUMC/(AUC)². Bioavailability (F) wasestimated using the equation F(%)=AUC_(ip)×Dose_(iv)/AUC_(iv)×Dose_(ip).

[0125] HPLC Analysis of Plasma HI-P131 Levels:

[0126] A highly sensitive quantitative HPLC detection method (Chen etal., 1998, J. Chromatography B (Biomedical sciences), in press) was usedto determine the pharmocokinetics of HI-P131. In brief, the HPLC systemconsisted of a Hewlett Packard (HP) series 1100 equipped with anautomated electronic degasser, a quaternary pump, an autosampler, anautomatic thermostatic column compartment, diode array detector and acomputer with a Chemstation software program for data analysis. A 250×4mm Lichrospher 100, RP-18 (5 μm) analytical column and a 4×4 mmLichrospher 100, RP-18 (5 μm) guard column were obtained from HewlettPackard Inc. (San Fernando, Calif.). Acetonitrile/water containing 0.1%of trifluoroacetic acid (TFA) and 0.1% triethylamine (TEA) (28:72, v/v)was used as the mobile phase. The wavelength of detection was set at 340nm. Peak width, response time and slit were set at >0.03 minutes, 0.5seconds and 8 nm, respectively.

[0127] For determination of HI-P131 levels, 10 μL of internal standardHI-P154 (50 μM) was added to a 100 μL plasma sample. For extraction, 7ml chloroform was then added to the plasma sample, and the mixture wasvortexed thoroughly for 3 minutes. Following centrifugation (300×g, 5minutes), the aqueous layer was frozen using acetone/dry ice and theorganic phase was transferred into a clean test tube. The chloroformextracts were dried under a slow steady stream of nitrogen. The residuewas reconstituted in 100 μL of methanol: water (9:1) and 50 μL aliquotof this solution was used for HPLC analysis. Under the describedchromatographic separation conditions, the retention times for HI-P131and HI-P154 were 5.1 minutes and 9.5 minutes, respectively. At theretention time, HI-P131 and its internal standard HI-P154 were elutedwithout any interference peaks from the blank plasma.

[0128] HI-P131 was not toxic to mice at intraperitoneal single bolusdoses ranging from 0.5 mg/kg to 250 mg/kg. None of the 50 mice treatedwith HI-P1131 experienced side effects or died of toxicity during the 30day observation period. In particular, we observed no hematologic sideeffects such as neutropenia, lymphopenia, or anemia at the tested doselevels. No histopathologic lesions were found in the organs of HI-P131treated mice that were selectively killed at 30 days and there was nobone marrow hypoplasia or lymphoid cell depletion in spleen and lymphnodes. Thus, the maximum tolerated dose (MTD) of HI-P131 was not reachedat 250 mg/kg. We next examined the pharmacokinetic features of HI-P131in mice. A two-compartment pharmacokinetic model was fit to thepharmacokinetics data obtained following the intravenous (i.v.) orintraperitoneal (i.p.) administration of a single non-toxic 12.5 mg/kgbolus dose of HI-P131. The estimated maximum plasma concentrations(Cma.) of HI-P131 were 85.6 μM after i.v. administration.

Example 9 Antitumor Activity of Quinazolines In Vivo

[0129] To test the anti-tumor activity of quinazolines in vivo, cancercells were implanted and grown in mice in the presence of quinazoline.

[0130] Inhibition of Breast Cancer Cells

[0131] The left hind legs of CB.17 SCID mice were inoculatedsubcutaneously with 0.75×10⁶ MDA-MB-231 human breast cancer cells in 0.1ml PBS. Twenty-four hours after inoculation, the mice were treated withHI-P353 (10 mg/kg/day x 5 days/week, N=7), or HI-P364 (10 mg/kg/day×5days/week, N=8), or vehicle (50% DMSO in PBS, N=7) for four weeks. Themice were monitored daily for health status and tumor growth.Measurements were taken on the tumors 3 times a week using a Verniercaliper. Tumor volumes were calculated using the following formula:(width)²×(length/2). Comparisons of the outcomes of the three groupswere done using the log-rank test.

[0132] The data are shown in FIG. 10A, and demonstrate that treatment ofanimals with the quinazolines of the invention (HI-P353 and HI-P364)inhibited the growth of breast cancer cell tumors as compared withuntreated controls.

[0133] Inhibition of Brain Tumor Cells

[0134] An analogous experiment was done implanting brain tumor cellsinto mice. The right hind legs of CB.17 SCID mice were inoculatedsubcutaneously with 1×10⁶ of U373 human glioblastoma cells in 0.1 ml ofPBS. Twenty four hours after inoculation, mice were treated with HI-P353(10 mg/kg/day×5 days/week, N=7), or HI-P364 (10 mg/kg/day×5 days/week,N=8), or vehicle (50% DMSO in PBS, N=7) for four weeks. Mice weremonitored daily for health status and tumor growth. Tumors were measured3 times a week using a Vernier caliper. Tumor volumes were calculatedusing the following formula: (width)²×(length/2). Comparisons of outcomebetween groups were done using the log-rank test.

[0135] The data are shown in FIG. 10B and demonstrate that treatment ofanimals with the quinazolines of the invention (HI-P353 and HI-P364)inhibited the growth of brain tumors as compared with untreatedcontrols.

[0136] Inhibition of Intracranial Brain Tumors

[0137] The anti-tumor activity of the quinazolines of the invention wasalso studied with intracranial tumors. Nude mice were first anesthetizedwith Avertin. Under aseptic conditions in a laminar flow hood, a smallhole was drilled at 2 mm to the right of the midline and 2 mm posteriorto the bregma. An amount of 4×10⁵ U87 glioblastoma cells in 10 μL of PBSwere intracranially implanted using a Hamilton syringe into the rightcerebral hemisphere of mice and a stereotaxic apparatus according to themethod described in Huang, H. J. S. et al., J. Biol. Chem.272:2927-2935, 1997.

[0138] Twenty-four hours after inoculation, mice were treated with1H—P353 (20 mg/kg/day×10 days, n=10), HI-P364 (20 mg/kg/day×10 days,n=10), or vehicle (50% DMSO in PBS, n=10). The mice were monitored twicedaily for health status.

[0139]FIG. 10C shows the survival rate of mice inflicted withintracranial tumors. Treatment of mice with quinazolines (HI-P353 andHI-P364) resulted in prolonged survival as compared with mice treatedwith vehicle alone.

[0140] All publications, patents, and patent documents described hereinare incorporated by reference as if fully set forth. The inventiondescribed herein may be modified to include alternative embodiments. Allsuch obvious alternatives are within the spirit and scope of theinvention, as claimed below.

We claim:
 1. A compound of the formula:

wherein: R^(a) is iodo, (C₁-C₄)hydroxyalkyl, methylenedioxy,ethylenedioxy, benzyloxy, OCF₃. SCF₃SO₃H, SO₂F, SO₂NR²R³ where R² ishydrogen or (C₁-C₄)alkyl and R³ is hydrogen, (C₁₋C₄)alkyl, or phenyl,NR²R⁴ where R² is hydrogen or (C₁-C₄)alkyl and R⁴ is phenyl; or a groupof the formula

wherein R⁵ and R⁶ are each independently, hydrogen, (C₁-C₄)alkyl, or(C₁-C₄) perfluoroalkyl, and R⁷ is hydrogen, halo, hydroxy, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)hydroxyalkyl, or N(R²)₂, where R² is hydrogen or(C₁-C₄)alkyl; n is an integer of 1-4; R^(b) is each, independently,hydrogen, halo, hydroxy, mercapto, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)thioalkyl, (C₁-C₄)hydroxyalkyl, nitro, cyano, methylenedioxy,ethylenedioxy, COCH_(3,) CF_(3,) OCF_(3,) SCF_(3,) COOH, SO₃H, SO₂F,phenyl, or phenyl substituted by a group selected from halo, hydroxy,mercapto, (C₁-C₄)alkyl, (C₁-C₄) alkoxy, (C₁-C₄)thioalkyl,(C₁-C₄)hydroxyalkyl, amino, nitro, cyano, CF₃, COOH, SO₃H, SO₂NR²R³,SO₂F where R² is H or (C₁-C₄)alkyl and R³ is H, (C₁-C₄)alkyl, phenyl, orphenyl substituted by a group as defined above; benzyloxy or benzyloxysubstituted on the phenyl portion by a group defined above; NR²R³ whereR² is H or (C₁-C₄)alkyl and R³ is H, (C₁-C₄)alkyl, phenyl, or phenylsubstituted by a group as defined above; and R¹ is (C₁-C₄)alkyl or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein the pharmaceutically acceptable salt is an acid addition salt.3. The compound of claim 1, wherein R¹ is methyl.
 4. The compound ofclaim 3, wherein R^(a) is a member selected from the group consisting ofI, NHC₆H₅, —OCH₂CH₂O—, —OCH₂O—, OCF₃, SCF₃, CH₂OH, C₂H₄OH, SO₃H, SO₂NH₂,and SO₂F.
 5. The compound of claim 4, wherein R^(a) is I, OCF_(3,) orSO₂F.
 6. The compound of claim 5, wherein R^(a) is I.
 7. The compound ofclaim 5 wherein R^(a) is OCF₃.
 8. The compound of claim 3, wherein n isI and R^(a) is a group of the formula


9. The compound of claim 8, wherein R⁵ and R⁶ are each, independently,H, CH_(3,) or CF₃.
 10. The compound of claim 9, wherein R⁵ and R⁶ areCF₃ and R⁷ is NH₂.
 11. The compound of claim 3, wherein R^(b) is atleast one member selected from the group consisting of F, Cl, Br, I, OH,NH₂, NO₂, CN, COOH, CH₃ and CF₃.
 12. The compound of claim 11, whereinR^(b) is at least one member selected from the group consisting of F,Cl, Br, OH and CF₃.
 13. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier or diluent.
 14. A method of treatingtumors in a subject comprising administering to said subject ananti-tumor effective amount of a compound of claim
 1. 15. A method oftreating leukemia in a subject comprising administering to said subjecta compound of claim 1 in an amount effective for inducing apoptosis ofleukemia cells.
 16. A method of inhibiting cancer cell growth in asubject comprising administering to said subject a cytotoxic effectiveamount of a compound of claim
 1. 17. A method of treating leukemia in asubject comprising administering to said subject a compound selectedfrom the group consisting of:4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline,4-(2′,4′,6′-tribromophenyl)amino-6,7-dimethoxyquinazoline,4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,4-(3′-fluorophenyl)amino-6,7-dimethoxyquinazoline,4-(2′-fluorophenyl)amino-6,7-dimethoxyquinazoline,4-(4′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,4-(2′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline, andpharmaceutically acceptable acid addition salts thereof.
 18. A method oftreating breast tumors in a subject comprising administering to saidsubject a compound selected from the group consisting of4-(3′-bromophenyl)amino-6,7-dimethoxyquinazoline,4-(3′,5′-dibromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(3′-chloro-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,4-(3′-fluorophenyl)amino-6,7-dimethoxyquinazoline,4-(2′-fluorophenyl)amino-6,7-dimethoxyquinazoline, and pharmaceuticallyacceptable acid addition salts thereof.
 19. A method of treatingmulti-drug resistant leukemia in a subject comprising administering tosaid subject 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline or apharmaceutically acceptable salt thereof, in an amount effective forinducing apoptosis of multi-drug resistant leukemia cells.
 20. A methodof treating multi-drug resistant leukemia in a subject comprisingadministering to said subject4-(3′-bromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline or apharmaceutically acceptable acid addition salt thereof, in an amounteffective for inducing apoptosis of multi-drug resistant leukemia cells.21. The compound4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline or apharmaceutically acceptable acid addition salt thereof.
 22. The compound4-2′,4′,6′-tribromophenyl)amino6,7-dimethoxyquinazoline or apharmaceutically acceptable acid addition salt thereof.
 23. The compound4-(2′,3′,5′,6′-tetrafluoro-5′-bromophenyl)amino-6,7-dimethoxyquinazolineor a pharmaceutically acceptable acid addition salt thereof.
 24. Thecompound 4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline or apharmaceutically acceptable acid addition salt thereof.
 25. The compound4-(4′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline or apharmaceutically acceptable acid addition salt thereof.
 26. The compound4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxy-quinazoline or apharmaceutically acceptable acid addition salt thereof.
 27. Apharmaceutical composition comprising an effective amount of a compoundselected from the group consisting of:4-(3,5-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,4-(2′,4′,6′-tribromophenyl)amino-6,7-dimethoxyquinazoline,4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,4-(4′-tifluoromethylphenyl)amino-6,7-dimethoxyquinazoline, andpharmaceutically acceptable acid addition salts thereof; and apharmaceutically acceptable carrier or diluent.